This invention relates to aryl or heteroaryl fused imidazole compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of this invention have activity as prostaglandin E2 receptor antagonists, and these are useful in the treatment or alleviation of pain and inflammation and other inflammation-associated disorders, such as arthritis. treating or preventing disorders or medical conditions selected from pain, inflammatory diseases and the like.
Prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. Especially prostaglandin E2 (PGE2) is the predominant elcosanoid detected in inflammation conditions. In addition, it is also involved in various physiological and/or pathological conditions and such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acidsecretion, blood pressure, platelet function, bone metabolism, angiogenesis or the like.
Four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) displaying different pharmacological properties have been cloned. EP4 subtype, a Gs-coupled receptor stimulates cAMP production, and is distributed in a wide variety of tissue suggesting major role in PGE2-mediated biological events.
WO99/47497 discloses carboxylic acids and acylsulfonamides compounds as prostaglandin-receptor antagonists.
The present invention provides a compound of the following formula: 
or the pharmaceutically acceptable salts thereof, wherein
Y1, Y2, Y3 and Y4 are independently selected from N, CH or C(L);
R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo-substituted C1-8 alkoxy, C1-8 alkyl-S(O)m-, Q1xe2x80x94, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, C1-4alkyl-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94 or C1-4alkyl-S(O)m-N(R3)xe2x80x94, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl are optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1xe2x80x94, Q1xe2x80x94C(xe2x95x90O)xe2x80x94, Q1xe2x80x94Oxe2x80x94, Q1xe2x80x94S(O)m-, Q1xe2x80x94C1-4alkyl-Oxe2x80x94, Q1xe2x80x94C1-4alkyl-S(O)m-, Q1xe2x80x94C1-4alkyl-C(O)xe2x80x94N(R3)xe2x80x94, Q1xe2x80x94C1-4alkyl-N(R3)xe2x80x94 or C1-4alkyl-C(O)xe2x80x94N(R3)xe2x80x94;
Q1 is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94 or NH2(HNxe2x95x90)Cxe2x80x94;
A is a 5-6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-6 membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C-1-4 alkylsulfonyl, aminosulfonyl, acetyl, R3N(R4)C(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94 and NH2(HNxe2x95x90)Cxe2x80x94;
B is halo-substituted C1-6 alkylene, C3-7 cycloalkylene, C2-6 alkenylene, C2-6 alkynylene, xe2x80x94Oxe2x80x94C1-5 alkylene, C1-2 alkylene-Oxe2x80x94C1-2 alkylene or C16 alkylene optionally substituted with an oxo group or C1-3 alkyl;
W is NH, Nxe2x80x94C1-4 alkyl, O, S, Nxe2x80x94OR5 or a covalent bond;
R2 is H, C1-4 alkyl, OH or C1-4 alkoxy;
Z is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkyl(xe2x95x90O)xe2x80x94, R3C(xe2x95x90O)N(R4)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, NH2(HNxe2x95x90)Cxe2x80x94, Q2xe2x80x94S(O)m-, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94N(R3)xe2x80x94 or Q2xe2x80x94;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94, NH2(HNxe2x95x90)Cxe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, R3N(R4)S(O)m-, Q2xe2x80x94, Q2xe2x80x94C(xe2x95x90O)xe2x80x94, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94C1-4alkyl-Oxe2x80x94, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl
R5 is H, C1-4 alkyl, C1-4 alkyl-(Oxe2x95x90)Cxe2x80x94 or C1-4 alkyl-Oxe2x80x94(Oxe2x95x90)Cxe2x80x94; and
Q2 is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 5-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C11-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C-1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkyl-(Oxe2x95x90)Cxe2x80x94, R3(R4)C(xe2x95x90O)Nxe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94 or NH2(HNxe2x95x90)Cxe2x80x94.
The aryl or heteroaryl fused imidazole compounds of this invention have an antagonistic action towards prostaglandin and are thus useful in therapeutics, particularly for the treatment of a disorder or condition selected from the group consisting of pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, fibromyalgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing sspondylitis, bursitits, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures or bone fracture, immune and autoimmune diseases such as systemic lupus erythematosus; AIDS(acquired immuno deficiency syndrome), gastrointestinal cancers such as colon cancer ; cellular neoplastic transformations or metastic tumor growth; Diabetic retinopathy, tumor angiogenesis; prostanoid-induced smooth muscle contraction associated with dysmenorrhea, premature labor, allergic rhinitis, atopic dermatitis, asthma or eosinophil related disorders, Hyperimmunoglobulinaemia, Castleman""s disease, myeloma; Alzheimer""s disease, sleep disorders, endocrine disturbance; glaucoma; bone loss; osteoporosis; promotion of bone formation; Paget""s disease: cytoprotection in peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions; GI bleeding and patients undergoing chemotherapy; coagulation disorders selected from hypoprothrombinemia, haemophilia and other bleeding problems; kidney disease; thrombosis; occlusive vascular disease; presurgery; and anti-coagulation, or the like in mammalian, especially humans.
The present invention provides a pharmaceutical composition for the treatment of a disorder or condition mediated by prostaglandin, in a mammalian including a human, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention also provides a pharmaceutical composition for the treatment of a disorder or condition selected from the group consisting of pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, postpartum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, fibromyalgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing sspondylitis, bursitits, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures, bone fracture, immune and autoimmune diseases such as systemic lupus erythematosus; AIDS(acquired immuno deficiency syndrome), gastrointestinal cancers such as colon cancer; cellular neoplastic transformations or metastic tumor growth;
Diabetic retinopathy, tumor angiogenesis; prostanoid-induced smooth muscle contraction associated with dysmenorrhea, premature labor, allergic rhinitis, atopic dermatitis, asthma or eosinophil related disorders, Hyperimmunoglobulinaemia, Castleman""s disease, myeloma; Alzheimer""s disease, sleep disorders, endocrine disturbance; glaucoma; bone loss; osteoporosis; promotion of bone formation;
Paget""s disease: cytoprotection in peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions; GI bleeding and patients undergoing chemotherapy; coagulation disorders selected from hypoprothrombinemia, haemophilia and other bleeding problems; kidney disease;
thrombosis; occlusive vascular disease; presurgery; and anti-coagulation, or the like, which comprises a therapeutically effective amount of the aryl or heteroaryl fused imidazole compound of formula (I) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Also, the present invention provides a method for the treatment of a disorder or condition mediated by prostaglandin, in a mammalian including a human, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Further, the present invention provides a method for the treatment of pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, fibromyalgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing sspondylitis, bursitits, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures, bone fracture, immune and autoimmune diseases such as systemic lupus erythematosus; AIDS, gastrointestinal cancers such as colon cancer; cellular neoplastic transformations or metastic tumor growth; Diabetic retinopathy, tumor angiogenesis;
prostanoid-induced smooth muscle contraction associated with dysmenorrhea, premature labor, allergic rhinitis, atopic dermatitis, asthma or eosinophil related disorders, Hyperimmunoglobulinaemia, Castleman""s disease, myeloma; Alzheimer""s disease, sleep disorders, endocrine disturbance; glaucoma; bone loss; osteoporosis; promotion of bone formation; Paget""s disease: cytoprotection in peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions; GI bleeding and patients undergoing chemotherapy; coagulation disorders selected from hypoprothrombinemia, haemophilia and other bleeding problems; kidney disease; thrombosis; occlusive vascular disease;
presurgery; and anti-coagulation or the like, in a mammalian subject, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I).
Also, the present invention provides a pharmaceutical formulation comprising a compound of formula (I), a pharmaceutically acceptable carrier and, optionally, one or more other pharmacologically active ingredients.
Also, the present invention provides a pharmaceutical formulation comprising a compound of formula (I), a pharmaceutically acceptable carrier and, optionally, one or more other pharmacologically active ingredients selected from a COX-2 selective, COX-1 selective or non-selective NSAIDs(nonsteroidal anti-inflammatory drugs ), opioids, anticonvulsants, antidepressants, local anesthetics, disease-modifying anti-rheumatoid drugs, or steroids.
Also, the present invention provides a compound of the following formula: 
or salts thereof
wherein Y1, Y2, Y3 and Y4 are independently selected from N, CH or C(L);
R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo substituted
C1-8 alkoxy, C1-8 alkyl-S(O)m-, Q1xe2x80x94, amino, mono- or di-(C1-8 alkyl)amino, C1-4alkyl-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94 or C1-4alkyl-S(O)m-N(R3)xe2x80x94, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl are optionally substituted with halo, C1-3 alkyl, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, Q1xe2x80x94, Q1xe2x80x94C(xe2x95x90O)xe2x80x94, Q1xe2x80x94Oxe2x80x94, Q1xe2x80x94S(O)m-, Q1xe2x80x94C1-4alkyl-Oxe2x80x94, Q1xe2x80x94C1-4alkyl-S(O)m-, Q1xe2x80x94C1-4alkyl-C(O)xe2x80x94N(R3)xe2x80x94 or Q1xe2x80x94C1-4alkyl-N(R3)xe2x80x94;
Q1 is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94 or NH2(HNxe2x95x90)Cxe2x80x94;
A is a benzene ring optionally substituted with up to 3 substituents or pyridine ring optionally substituted with up to 3 substituents, wherein said substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, acetyl, R3N(R4)C(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94 and NH2(HNxe2x95x90)Cxe2x80x94;
B is C2-6 alkylene, C3-7 cycloalkylene, C2-6 alkenylene, or C2-6 alkynylene optionally substituted with C1-3 alkyl;
W is NH or O;
P is H, a protecting group, or Q3xe2x80x94OC(xe2x95x90O)xe2x80x94;
Q3 is a 6-10 membered monocyclic or bicyclic aromatic ring optionally substituted with halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, nitro, cyano, C1-4 alkylsulfonyl, C1-4alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, or C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94, NH2(HNxe2x95x90)Cxe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94 or R3N(R4)S(O)m-, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2; and
R3 and R4 are independently selected from H and C1-4 alkyl.
Also, the present invention provides a compound of the following formula: 
or salts thereof
wherein Y1, Y2, Y3 and Y4 are independently selected from N, CH or C(L);
R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo-substituted C1-8 alkoxy, C1-8 alkyl-S(O)m-, Q1xe2x80x94, amino, mono- or di-(C1-8 alkyl)amino, C1-4alkyl-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94 or C1-4alkyl-S(O)m-N(R3)xe2x80x94, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl are optionally substituted with halo, C1-3 alkyl, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, Q1xe2x80x94, Q1xe2x80x94C(xe2x95x90O)xe2x80x94, Q1xe2x80x94Oxe2x80x94, Q1xe2x80x94S(O)m-, Q1xe2x80x94C1-4alkyl-Oxe2x80x94, Q1xe2x80x94C1-4alkyl-S(O)m-, Q1xe2x80x94C1-4alkyl-C(O)xe2x80x94N(R3)xe2x80x94 or Q1xe2x80x94C1-4alkyl-N(R3)xe2x80x94;
Q1 is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94 or NH2(HNxe2x95x90)Cxe2x80x94;
A is a benzene ring optionally substituted with up to 3 substituents or pyridine ring optionally substituted with up to 3 substituents, wherein said substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, acetyl, R3N(R4)C(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94 and NH2(HNxe2x95x90)Cxe2x80x94;
B is C2-6 alkylene, C3-7 cycloalkylene, C2-6 alkenylene, or C2-6 alkynylene optionally substituted with C1-3 alkyl;
W is NH or O;
P is H, a protecting group, or Zxe2x80x94S(O)2xe2x80x94N(R2)xe2x80x94C(xe2x95x90O)xe2x80x94;
Z is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkyl(xe2x95x90O)xe2x80x94, R3C(xe2x95x90O)N(R4)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, NH2(HNxe2x95x90)Cxe2x80x94, Q2xe2x80x94S(O)m-, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94N(R3)xe2x80x94 or Q2xe2x80x94;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94, NH2(HNxe2x95x90)Cxe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94 or R3N(R4)S(O)m-, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0, 1 or 2; and
R2, R3, and R4 are independently selected from H and C1-4 alkyl.
The term xe2x80x9calkylxe2x80x9d, as used herein, means a straight or branched saturated monovalent hydrocarbon radical including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, neopentyl and the like.
The term xe2x80x9calkenylxe2x80x9d, as used herein, means a hydrocarbon radical having at least one double bond including, but not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl and the like.
The term xe2x80x9calkynylxe2x80x9d, as used herein, means a hydrocarbon radical having at least one triple bond including, but not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl and the like.
The term xe2x80x9chaloxe2x80x9d, as used herein, refers to F, Cl, Br or I, preferably F or Cl.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, means a saturated carbocyclic radical including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, means an O-alkyl group wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9cmonocyclic aromatic ringxe2x80x9d, as used herein, means a monocyclic aromatic carbocyclic or heterocyclic ring (and containing 0-4 heteroatoms selected from O, N and S) including, but not limited to, phenyl, pyrazolyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl and the like.
The term xe2x80x9cbicyclic aromatic ringxe2x80x9d, as used herein, means a monocyclic or bicyclic aromatic carbocyclic or heterocyclic ring (and containing 0-4 heteroatoms selected from O, N and S) including, but not limited to, naphthyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl quinoxalinyl and the like.
The term xe2x80x9calkylenexe2x80x9d, as used herein, means saturated hydrocarbon (straight chain or branched) wherein a hydrogen atom is removed from each of the terminal carbons such as methylene, ethylene, propylene, butylene, pentylene, hexylene and the like.
The term xe2x80x9ccycloalkylenexe2x80x9d, as used herein, means divalent cycloalkyl groups including, but not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and cycloheptylene and the like.
The term xe2x80x9calkenylenexe2x80x9d, as used herein, means a straight or branched hydrocarbon chain spacer radical having at least one double bond including, but not limited to, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHCHxe2x80x94, xe2x80x94CHxe2x95x90CHCH(CH3)xe2x80x94, and the like.
The term xe2x80x9calkynylenexe2x80x9d, as used herein, means a straight or branched hydrocarbon chain spacer radical having at least one triple bond including, but not limited to, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Cxe2x80x94Cxe2x89xa1CCH2xe2x80x94, xe2x80x94Cxe2x89xa1CCH(CH3)xe2x80x94, and the like.
The term xe2x80x9ctricyclic ringxe2x80x9d, as used herein, means a saturated carbocyclic radical including, but not limited to, adamantyl, tricyclo[5.2.1.02,6]decane, and the like.
The term xe2x80x9ctwo adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atomsxe2x80x9d, as used herein, means, but not limited to, xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2CH2xe2x80x94Oxe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, and the like.
The term xe2x80x9carylxe2x80x9d, as used herein, means aromatic radicals including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl and the like.
The term xe2x80x9cprotecting groupxe2x80x9d, as used herein, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley and Sons, 1991);
The term xe2x80x9ctreatingxe2x80x9d, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d as used herein refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
In the compounds of formula (I),
Y1, Y2, Y3, and Y4 are preferably independently selected from N, CH and C(L);
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, mono- or di-(C1-4 alkyl)amino, halo-substituted C1-4 alkoxy, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, R3N(R4)S(O)m-, Q2xe2x80x94, Q2xe2x80x94C(xe2x95x90O)xe2x80x94, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94C1-4alkyl-Oxe2x80x94, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 8-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl-(Oxe2x95x90)Cxe2x80x94, R3(R4)C(xe2x95x90O)Nxe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl or C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94, more preferably Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl , hydroxy, C1-4 alkoxy, mono- or di-(C1-4 alkyl)amino, halo-substituted C1-4 alkoxy, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, R3N(R4)S(O)m-, Q2xe2x80x94, Q2xe2x80x94C(xe2x95x90O)xe2x80x94, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94C1-4alkyl-Oxe2x80x94, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring, or a 8-12 membered tricyclic ring containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo, more preferably Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
m is 0 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is 5 or 6 membered monocyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing 1 sulfur atom wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo, more preferably Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, cyano, HOxe2x80x94C1-4 alkyl, acetyl, R3N(R4)C(xe2x95x90O)xe2x80x94, R3N(R4)S(O)m-, Q2xe2x80x94, Q2xe2x80x94C(xe2x95x90O)xe2x80x94, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94C1-4alkyl-Oxe2x80x94, or two adjacent L groups are joined together to form a methylenedioxy group;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is 5 or 6 membered monocyclic aromatic ring system, more preferably Y1, Y2, Y3, and Y4 are independently selected from N, CH and Cxe2x80x94L;
L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, xe2x80x94C(xe2x95x90O)NH2, trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group, more preferably Y1, Y2, Y3 and Y4 are selected from the group consisting of
a) Y1 and Y3 are C(L), Y2 is CH and Y4 is N;
b) Y1 is CH, Y2 and Y3 are C(L) and Y4 is N;
c) Y1, Y2 and Y3 are C(L)and Y4 is N;
d) Y1 and Y3 are C(L), Y2 is N and Y4 is CH;
e) Y1 is C(L) and Y2, Y3 and Y4 are CH;
f) Y1, Y3 and Y4 are CH, and Y2 is C(L);
g) Y1, Y2 and Y3 are CH, and Y4 is C(L);
h) Y1 and Y2 are C(L), and Y3 and Y4 are CH;
i) Y1 and Y3 are C(L), and Y2 and Y4 are CH;
j) Y1 and Y4 are CH, and Y2 and Y3 are C(L);
k) Y1 and Y2 are CH, Y3 is C(L) and Y4 is N;
l) Y1 and Y3 are CH, Y2 is C(L) and Y4 is N;
m) Y1, Y2, Y3 and Y4 are CH;
n) Y1 and Y2 are C(L), Y3 is CH and Y4 is N;
o) Y1, Y2 and Y4 are CH, and Y3 is C(L);
p) Y1 and Y2 are C(L), Y3 is N and Y4 is CH;
q) Y1 and Y3 are C(L), and Y2 and Y4 are N;
r) Y1 is C(L), Y2 and Y3 are CH, and Y4 is N;
s) Y2 is C(L), Y1 and Y3 are CH, and Y4 is N; and
t) Y1, Y2 and Y3 are C(L), and Y4 is CH
L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, xe2x80x94C(xe2x95x90O)NH2, trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group, most preferably Y1, Y2, Y3 and Y4 are selected from the group consisting of
a) Y1 and Y3 are C(L), Y2 is CH and Y4 is N;
b) Y1 is CH, Y2 and Y3 are C(L) and Y4 is N;
c) Y1, Y2 and Y3 are C(L) and Y4 is N;
d) Y1 and Y3 are C(L), Y2 is N and Y4 is CH;
e) Y1 is C(L) and Y2, Y3 and Y4 are CH;
f) Y1, Y3 and Y4 are CH, and Y2 is C(L);
g) Y1, Y2 and Y3 are CH, and Y4 is C(L);
h) Y1 and Y2 are C(L), and Y3 and Y4 are CH;
i) Y1 and Y3 are C(L), and Y2 and Y4 are CH;
j) Y1 and Y4 are CH, and Y2 and Y3 are C(L); and
k) Y1, Y2 and Y3 are C(L), and Y4 is CH
L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, xe2x80x94C(xe2x95x90O)NH2, trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
In the compounds of formula (I),
R1 is preferably H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo-substituted C1-8 alkoxy, C1-8 alkyl-S(O)m-, Q1xe2x80x94, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, C1-4alkyl-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94 or C1-4alkyl-S(O)m-N(R3)xe2x80x94, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl are optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1xe2x80x94, Q1C(xe2x95x90O)xe2x80x94, Q1xe2x80x94Oxe2x80x94, Q1xe2x80x94S(O)m, Q1xe2x80x94C1-4 alkyl-Oxe2x80x94, Q1xe2x80x94C1-4 alkyl-S(O)m-, Q1xe2x80x94C1-4alkyl-C(O)xe2x80x94N(R3)xe2x80x94, Q1xe2x80x94C1-4alkyl-N(R3)xe2x80x94 or C1-4alkyl-C(O)xe2x80x94N(R3)xe2x80x94;
Q1 is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(O)Cxe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94 or NH2(HNxe2x95x90)Cxe2x80x94;
m is 0 or 2; and
R3 is H or C1-4 alkyl, more preferably R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, Q1xe2x80x94, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, wherein said C1-8 alkyl is optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1xe2x80x94, Q1xe2x80x94C(O)xe2x80x94, Q1xe2x80x94Oxe2x80x94, Q1xe2x80x94Sxe2x80x94 or Q1xe2x80x94C1-4 alkyl-Oxe2x80x94, or C1-4alkyl-C(O)xe2x80x94N(R3)xe2x80x94;
Q1 is a 5-12 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S, and is optionally substituted with halo, C1-4 alkyl, C1-4 alkylsulfonyl and C1-4 alkyl(xe2x95x90O)xe2x80x94; and
m is 0 or 2, more preferably R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, Q1xe2x80x94, or mono- or di-(C1-8 alkyl)amino wherein said C1-8 alkyl is optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1xe2x80x94, Q1xe2x80x94C(xe2x95x90O)xe2x80x94, Q1xe2x80x94Oxe2x80x94, Q1xe2x80x94Sxe2x80x94, Q1xe2x80x94C1-4 alkyl-Oxe2x80x94, or C1-4alkyl-C(O)xe2x80x94N(H)xe2x80x94;
Q1 is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S; and
m is 0 or 2, more preferably R1 is C1-5 alkyl, C3-7 cycloalkyl, or Q1xe2x80x94, mono- or di-(C1-8 alkyl)amino wherein said C1-5 alkyl is optionally substituted with C1-3 alkyl, hydroxy, oxo, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1xe2x80x94, or C1-4alkyl-C(O)xe2x80x94N(H)xe2x80x94; and
Q1 is 5-12 membered monocyclic aromatic ring system optionally containing up to 2 heteroatoms selected from N and S, more preferably R1 is C1-5 alkyl, mono- or di-(C1-8 alkyl)amino, pyrrolidinyl, or pyridyl optionally substituted with C1-3 alkyl, hydroxy, oxo, 5 or 6 membered monocyclic aromatic ring, wherein said 5 or 6 membered monocyclic aromatic ring is containing 1 or 2 heteroatoms selected from N and S, or C1-4alkyl-C(O)xe2x80x94N(H)xe2x80x94, most preferably R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl.
In the compounds of formula (I),
R2 is preferably H or C1-4 alkyl, most preferably H.
In the compounds of formula (I),
A is preferably a 5-6 membered monocyclic aromatic ring optionally containing up to 2 heteroatoms selected from O, N, and S, wherein said 5-6 membered monocyclic aromatic ring is optionally substituted with up to 2 substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy and halo-substituted C1-4 alkoxy, more preferably 5-6 membered monocyclic aromatic ring optionally substituted with halo, C1-4 alkyl or C1-4 alkoxy, more preferably 5-6 membered monocyclic aromatic ring system optionally substituted with halo or C1-4 alkyl, more preferably 5-6 membered monocyclic aromatic ring system, most preferably phenyl or pyridyl.
In the compounds of formula (I),
B is preferably C3-7 cycloalkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl, more preferably C1-3 alkylene optionally substituted with C1-3 alkyl, more preferably C1-2 alkylene optionally substituted with methyl, most preferably ethylene or propylene.
In the compounds of formula (I),
W is preferably NH, Nxe2x80x94C1-4 alkyl, O or Nxe2x80x94OH, more preferably NH, Nxe2x80x94C1-2 alkyl or O, most preferably NH, Nxe2x80x94CH3 or O.
In the compounds of formula (I),
Z is preferably a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from, N, O, and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, hydroxy, C1-4 alkoxy, nitro, amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl(xe2x95x90O)xe2x80x94, R3C(xe2x95x90O)N(R4)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94, Q2xe2x80x94S(O)m-, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94N(R3)xe2x80x94 or Q2xe2x80x94;
m is 0 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 8-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1 1-4 alkyl-(Oxe2x95x90)Cxe2x80x94, R3(R4)C(xe2x95x90O)Nxe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl or C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94, more preferably Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy, nitro, amino, cyano, R3C(xe2x95x90O)N(R4)xe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, Q2xe2x80x94S(O)m-, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94N(R3)xe2x80x94 or Q2xe2x80x94;
m is 0 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring, or a 8-12 membered tricyclic ring containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo, more preferably Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy, nitro, amino, cyano, R3C(xe2x95x90O)N(R4)xe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, Q2xe2x80x94S(O)m-, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94N(R3)xe2x80x94 or Q2xe2x80x94;
m is 0 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is 5 or 6 membered monocyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing 1 sulfur atom wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo, more preferably Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-12 membered monocyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, nitro, R3C(xe2x95x90O)N(R4)xe2x80x94 or Q2xe2x80x94;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is 5 or 6 membered monocyclic aromatic ring system, more preferably Z is 5-10 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-10 membered monocyclic aromatic ring is optionally substituted with chloro, bromo, methyl, nitro, CH3C(xe2x95x90O)NHxe2x80x94, tBuC(xe2x95x90O)NHxe2x80x94 or phenyl, most preferably Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl.
A preferred group of compounds of the present invention includes compounds of formula (I) wherein
Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, C1-8 alkoxy, halo-substituted C1-8 alkoxy, C1-8 alkyl-S(O)m-, Q1xe2x80x94, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, C1-4alkyl-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94 or C1-4alkyl-S(O)m-N(R3)xe2x80x94, wherein said C1-8 alkyl, C2-8 alkenyl and C2-8 alkynyl are optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1xe2x80x94, Q1xe2x80x94C(xe2x95x90O)xe2x80x94, Q1xe2x80x94Oxe2x80x94, Q1xe2x80x94S(O)m-, Q1xe2x80x94C1-4 alkyl-Oxe2x80x94, Q1xe2x80x94C1-4 alkyl-S(O)m-, Q1xe2x80x94C1-4alkyl-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94, or C1-4alkyl-C(xe2x95x90O)xe2x80x94N(R3)xe2x80x94;
Q1 is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl , hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, nitro, amino, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(O)Cxe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94 or NH2(HNxe2x95x90)Cxe2x80x94;
A is a 5-6 membered monocyclic aromatic ring optionally containing up to 2 heteroatoms selected from O, N, and S, wherein said 5-6 membered monocyclic aromatic ring is optionally substituted with up to 2 substituents selected from halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy and halo-substituted C1-4 alkoxy;
B is C3-7 cycloalkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl;
W is NH, Nxe2x80x94C1-4 alkyl, O or Nxe2x80x94OH;
R2 is H or C1-4 alkyl;
Z is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, hydroxy, C1-4 alkoxy, nitro, amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl(xe2x95x90O)xe2x80x94, R3C(xe2x95x90O)N(R4)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C1-4alkyl-C(xe2x95x90O)NHxe2x80x94, Q2xe2x80x94S(O)m-, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94N(R3)xe2x80x94 or Q2xe2x80x94;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl , hydroxy, C1-4 alkoxy, mono- or di-(C1-4 alkyl)amino, halo-substituted C1-4 alkoxy, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, R3N(R4)S(O)m-, Q2xe2x80x94; Q2xe2x80x94C(xe2x95x90O)xe2x80x94, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94C1-4alkyl-Oxe2x80x94, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 8-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, C1-4 alkylthio, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl-(Oxe2x95x90)Cxe2x80x94, R3(R4)C(xe2x95x90O)Nxe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl or C1-4 alkyl-C(xe2x95x90O)NHxe2x80x94.
A further preferred group of compounds of the present invention includes compounds of formula (I) wherein
Y1, Y2, Y3, and Y4 are independently selected from N, CH and C(L);
R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-7 cycloalkyl, Q1xe2x80x94, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C1-8 alkyl)amino, wherein said C1-8 alkyl is optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1xe2x80x94, Q1xe2x80x94C(O)xe2x80x94, Q1xe2x80x94Oxe2x80x94, Q1xe2x80x94Sxe2x80x94, Q1xe2x80x94C1-4 alkyl-Oxe2x80x94, or C1-4alkyl-C(O)xe2x80x94N(R3)xe2x80x94;
Q1 is a 5-12 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S, and is optionally substituted with halo, C1-4 alkyl, C1-4 alkylsulfonyl and C1-4 alkyl(xe2x95x90O)xe2x80x94;
A is 5-6 membered monocyclic aromatic ring optionally substituted with halo, C1-4 alkyl or C1-4 alkoxy;
B is C3-7 cycloalkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl;
W is NH, Nxe2x80x94C1-4 alkyl, O or Nxe2x80x94OH;
R2 is H or C1-4 alkyl;
Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy, nitro, amino, cyano, R3C(xe2x95x90O)N(R4)xe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, Q2xe2x80x94S(O)m-, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94N(R3)xe2x80x94 or Q2xe2x80x94;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl , hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, mono- or di-(C1-4 alkyl)amino, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl(xe2x95x90O)xe2x80x94, HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)N(R4)xe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, R3N(R4)S(O)m-, Q2xe2x80x94, Q2xe2x80x94C(xe2x95x90O)xe2x80x94, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94C1-4alkyl-Oxe2x80x94, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is a 5 or 6 membered monocyclic aromatic ring, or a 8-12 membered tricyclic ring containing up to 3 heteroatoms selected from N and S, wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo.
A further preferred group of compounds of the present invention includes compounds of formula (I) wherein
Y1, Y2, Y3 and Y4 are independently selected from N, CH and C(L);
R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl or C3-7 cycloalkyl, wherein said C1-8 alkyl is optionally substituted with halo, C1-3 alkyl, hydroxy, oxo, C1-4 alkoxy-, C1-4 alkyl-S(O)m-, C3-7 cycloalkyl-, cyano, indanyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1xe2x80x94, Q1xe2x80x94C(xe2x95x90O)xe2x80x94, Q1xe2x80x94, Q1xe2x80x94Sxe2x80x94, Q1xe2x80x94C1-4 alkyl-Oxe2x80x94, or C1-4alkyl-C(O)xe2x80x94N(R3)xe2x80x94;
Q1 is a 5 or 6 membered monocyclic aromatic ring optionally containing up to 4 heteroatoms selected from N and S;
A is 5-6 membered monocyclic aromatic ring system optionally substituted with halo or C1-4 alkyl;
B is or C3-7 cycloalkylene or C1-6 alkylene optionally substituted with an oxo group or C1-3 alkyl;
W is NH, Nxe2x80x94C1-4 alkyl, O or Nxe2x80x94OH;
R2 is H or C1-4 alkyl;
Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, halo-substituted C1-4 alkyl, C1-4 alkenyl, C1-4 alkoxy, nitro, amino, cyano, R3C(xe2x95x90O)N(R4)xe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, Q2xe2x80x94S(O)m-, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94N(R3)xe2x80x94 or Q2xe2x80x94;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl, hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, cyano, HOxe2x80x94C1-4 alkyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkyl(xe2x95x90O), HO(Oxe2x95x90)Cxe2x80x94, C1-4 alkyl-O(Oxe2x95x90)Cxe2x80x94, C1-4 alkylsulfonylamino, C3-7 cycloalkyl, R3C(xe2x95x90O)NR4xe2x80x94, R3N(R4)C(xe2x95x90O)xe2x80x94, R3N(R4)S(O)m-, Q2xe2x80x94, Q2xe2x80x94C(xe2x95x90O)xe2x80x94, Q2xe2x80x94Oxe2x80x94, Q2xe2x80x94C1-4alkyl-Oxe2x80x94, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;
m is 0 or 2;
R3 and R4 are independently selected from H and C1-4 alkyl; and p1 Q2 is 5 or 6 membered monocyclic aromatic ring or a 8-12 membered tricyclic ring optionally containing 1 sulfur atom wherein said 5 or 6 membered monocyclic aromatic ring is optionally substituted with halo.
A further preferred group of compounds of the present invention includes compounds of formula (I) wherein
Y1, Y2, Y3 and Y4 are independently selected from N, CH and C(L);
R1 is C1-5 alkyl or C3-7 cycloalkyl, wherein said C1-5 alkyl is optionally substituted with C1-3 alkyl, hydroxy, oxo, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q1xe2x80x94, or C1-4alkyl-C(O)xe2x80x94N(H)xe2x80x94;
Q1 is 5-12 membered monocyclic aromatic ring system optionally containing up to 2 heteroatoms selected from N and S,
A is 5-6 membered monocyclic aromatic ring system;
B is C1-3 alkylene optionally substituted with C1-3 alkyl;
W is NH, Nxe2x80x94C1-2 alkyl or O;
R2 is H;
Z is 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-12 membered monocyclic aromatic ring is optionally substituted with halo, C1-4 alkyl, nitro, R3C(xe2x95x90O)N(R4)xe2x80x94 or Q2xe2x80x94;
L is halo, C1-4 alkyl, halo-substituted C1-4 alkyl , hydroxy, C1-4 alkoxy, halo-substituted C1-4 alkoxy, cyano, HOxe2x80x94C1-4 alkyl, acetyl, R3N(R4)C(xe2x95x90O)xe2x80x94, R3N(R4)S(O)m-, Q2xe2x80x94, Q2xe2x80x94C(xe2x95x90O)xe2x80x94, or two adjacent L groups are joined together to form a methylenedioxy group;
R3 and R4 are independently selected from H and C1-4 alkyl; and
Q2 is 5 or 6 membered monocyclic aromatic ring system.
A further preferred group of compounds of the present invention includes compounds of formula (I) wherein
Y1, Y2, Y3 and Y4 are independently selected from N, CH and Cxe2x80x94L;
R1 is C1-5 alkyl optionally substituted with C1-3 alkyl, hydroxy, oxo, 5 or 6 membered monocyclic aromatic ring, wherein said 5 or 6 membered monocyclic aromatic ring is containing 1 or 2 heteroatoms selected from N and S, or C1-4alkyl-C(O)xe2x80x94N(R3)xe2x80x94;
A is phenyl;
B is C1-2 alkylene optionally substituted with methyl;
W is NH, Nxe2x80x94CH3 or O;
R2 is H;
Z is 5-10 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from N and S, wherein said 5-10 membered monocyclic aromatic ring is optionally substituted with chloro, bromo, methyl, nitro, CH3C(xe2x95x90O)NHxe2x80x94, tBuC(xe2x95x90O)NHxe2x80x94 or phenyl; and
L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, xe2x80x94C(xe2x95x90O)NH2, trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
A further preferred group of compounds of the present invention includes compounds of formula (I) wherein
Y1, Y2, Y3 and Y4 are independently selected from N, CH and Cxe2x80x94L;
R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
A is phenyl;
B is ethylene or propylene;
W is NH, Nxe2x80x94CH3 or O;
R2is H;
Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl; and
L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, xe2x80x94C(xe2x95x90O)NH2, trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
A further preferred group of compounds of the present invention includes compounds of formula (I) wherein
Y1, Y2, Y3 and Y4 are selected from the group consisting of
a) Y1 and Y3 are C(L), Y2 is CH and Y4 is N;
b) Y1 is CH, Y2 and Y3 are C(L) and Y4 is N;
c) Y1, Y2 and Y3 are C(L) and Y4 is N;
d) Y1 and Y3 are C(L), Y2 is N and Y4 is CH;
e) Y1 is C(L) and Y2, Y3 and Y4 are CH;
f) Y1, Y3 and Y4 are CH, and Y2 is C(L);
g) Y1, Y2 and Y3 are CH, and Y4 is C(L);
h) Y1 and Y2 are C(L), and Y3 and Y4 are CH;
i) Y1 and Y3 are C(L), and Y2 and Y4 are CH;
j) Y1 and Y4 are CH, and Y2 and Y3 are C(L);
k) Y1 and Y2 are CH, Y3 is C(L) and Y4 is N;
l) Y1 and Y3 are CH, Y2 is C(L) and Y4 is N;
m) Y1, Y2, Y3 and Y4 are CH;
n) Y1 and Y2 are C(L), Y3 is CH and Y4 is N;
o) Y1, Y2 and Y4 are CH, and Y3 is C(L);
p) Y1 and Y2 are C(L), Y3 is N and Y4 is CH;
q) Y1 and Y3 are C(L), and Y2 and Y4 are N;
r) Y1 is C(L), Y2 and Y3 are CH, and Y4 is N; and
s) Y2 is C(L), Y1 and Y3 are CH, and Y4 is N;
R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
A is phenyl;
B is ethylene or propylene;
W is NH, Nxe2x80x94CH3 or O;
R2is H;
Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl; and
L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, xe2x80x94C(xe2x95x90O)NH2, trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
A further preferred group of compounds of the present invention includes compounds of formula (I) wherein
Y1, Y2, Y3 and Y4 are selected from the group consisting of
a) Y1 and Y3 are C(L), Y2 is CH and Y4 is N;
b) Y1 is CH, Y2 and Y3 are C(L) and Y4 is N;
c) Y1, Y2 and Y3 are C(L) and Y4 is N;
d) Y1 and Y3 are C(L), Y2 is N and Y4 is CH;
e) Y1 is C(L) and Y2, Y3 and Y4 are CH;
f) Y1, Y3 and Y4 are CH, and Y2 is C(L);
g) Y1, Y2 and Y3 are CH, and Y4 is C(L);
h) Y1 and Y2 are C(L), and Y3 and Y4 are CH;
i) Y1 and Y3 are C(L), and Y2 and Y4 are CH; and
j) Y1 and Y4 are CH, and Y2 and Y3 are C(L);
R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;
A is phenyl;
B is ethylene or propylene;
W is NH, Nxe2x80x94CH3 or O;
R2 is H;
Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl; and
L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, xe2x80x94C(xe2x95x90O)NH2, trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.
Preferred individual compounds of this invention are following:
3-(4-{2-[({[(5-chloro-1,3-dimethyl-1h-pyrazol-4-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
3-(4-{2-[({[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
N-[5-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)-1,3,4-thiadiazol-2-yl]acetamide;
6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole;
6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
2-ethyl-5,7-dimethyl-3-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]aminocarbonyl)amino]propyl}phenyl)-3H-imidazo[4,5-b]pyridine;
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]-1-methylethyl(4-methylphenyl)sulfonylcarbamate;
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-propyl-3H-imidazo[4,5-b]pyridine;
2-isopropyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
2-butyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
2-isobutyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]aminocarbonyl)amino]ethyl}phenyl)-2-neopentyl-3H-imidazo[4,5-b]pyridine;
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine;
3-{4-[2-({[(4-biphenylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
2-ethyl-5,7-dimethyl-3-{4-[2-({[(1-naphthylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine;
2-ethyl-5,7-dimethyl-3-{4-[2-({[(2-naphthylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-3H-imidazo[4,5-b]pyridine;
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
3-(4-{2-[({[(4,5-dichloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
3-{4-[2-({[(1-benzothien-2-ylsulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
5-chloro-2-ethyl-7-methyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
6-cyano-2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine;
4-methyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;
7-chloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benimidazole;
5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;
5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;
5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
2-ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
2-ethyl-4,5-dimethyl-1-(4-2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
4,6-dimethyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;
5,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
5,6-dichloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
2-[4-(5,6-dichloro-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl-(4-methylphenyl)sulfonyl carbamate;
6-chloro-5-trifluoromethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonyl carbamate;
5-chloro-6-methyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;
2-ethyl-3-{4-[2-({[({3-[hydroxy(oxido)amino]phenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
3-(4-{2-[({[(4-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
n-[4-({[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]amino}sulfonyl)phenyl]-2,2-dimethylpropanamide;
3-(4-(2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
3-(4-(2-[({[(3-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7dimethyl-3H-imidazo[4,5-b]pyridine;
3-(4-{2-[({[(5-chloro-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
3-(4-{2-[({[(5-bromo-2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
3-(4-{2-[({[(2-bromophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
3-{4-[2-({[({4-chloro-3-nitrophenyl}sulfonyl)amino]carbonyl}amino)ethyl]phenyl}-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl-(4-methylphenyl)sulfonyl carbamate;
2-(4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
N-{[(2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
2-ethyl-4,6-dimethyl-1-(4-2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(2-chlorophenyl)sulfonylcarbamate;
2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethyl-4-methylphenyl)sulfonylcarbamate;
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(5-methyl-2-pyridinyl)sulfonylcarbamate;
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
2-{4-[5-(aminocarbonyl)-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
N-{[(2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-2-thiophenesulfonamide;
2-[4-(4,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonylcarbamate;
2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl )-1H-benzimidazol-1-yl]phenyl}-1-methylethyl(4-methylphenyl)sulfonylcarbamate;
2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
N-([(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl (4-methylphenyl)sulfonylcarbamate;
6-chloro-2-ethyl-1-(4-{2-[methyl({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide; and
salts thereof.
Most preferred individual compounds of this invention are following:
6-ethyl-5-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-5H-[1,3]dioxolo[4,5-f]benzimidazole;
6-chloro-5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenylsulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5b]pyridin-3-yl)phenyl]-1-methylethyl-(4-methylphenyl)sulfonylcarbamate;
5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-[2-(1,3-thiazol-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine;
2-ethyl-5,7-dimethyl-3-(4-{2-[({[(2-thienyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
3-(4-{2-[({[(2-chlorophenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine;
2-ethyl-5,6-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl )amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
5,6-dichloro-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine;
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine;
5-methoxy-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;
5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole;
5-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
2-ethyl-5-hydroxy-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
2-ethyl-4,5-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]aminocarbonyl)amino]ethyl}phenyl)-1H-benzimidazole;
4-(6-chloro-2-ethyl-5-trifluoromethyl-1H-benzimidazol-1-yl)phenethyl-(4-methylphenyl)sulfonylcarbamate; and
6-chloro-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;
2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl(4-methylphenyl)sulfonylcarbamate;
2-{4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
N-{[(2-(4-[5,7-dimethyl-2-(methylamino)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
N-{[(2-{4-[2-ethyl-5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide;
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl (2-chlorophenyl)sulfonylcarbamate;
2-{5-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-2-pyridinyl}ethyl-4-methylphenyl)sulfonylcarbamate;
2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(5-methyl-2-pyridinyl)sulfonylcarbamate;
2-{4-[6-chloro-2-(1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
2-{4-[6-chloro-2-(4-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
2-{4-[5-(aminocarbonyl )-6-chloro-2-ethyl-1H-benzimidazol-1-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
N-{[(2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl )-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
2-{4-[6-chloro-2-ethyl-5-(methylsulfonyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-2-thiophenesulfonamide;
2-[4-(4 ,6-dimethyl-2-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl-(4-methylphenyl)sulfonylcarbamate;
2-[4-(2-butyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl-(4-methylphenyl)sulfonylcarbamate;
2-(4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonylcarbamate;
2-{4-[4,6-dimethyl-2-(3-phenylpropyl)-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
2-{4-[6-chloro-2-(2-pyridinyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
(1S)-2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-1-methylethyl-(4-methylphenyl)sulfonylcarbamate;
2-{6-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]-3-pyridinyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
N-{[(2-{4-[6-chloro-2-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
N-{[(2-{4-[5,7-dimethyl-2-(1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide;
2-{4-[2-(1,1-dimethylethyl)-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]phenyl}ethyl-(4-methylphenyl)sulfonylcarbamate;
2-{4-[2-[1-(acetylamino)-1-methylethyl]-6-chloro-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl(4-methylphenyl)sulfonylcarbamate;
6-chloro-2-ethyl-1-(4-{2-[methyl ({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole-5-carboxamide; and
salts thereof.
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, Y1 to Y4, R1 to R7, A, B, W, Z, L, m, P, Q1 and Q2 in the reaction Schemes and discussion that follow are defined herein before.
The aryl or heteroaryl fused imidazole compounds of Formula (I) of this invention may be prepared by a variety of synthetic methods known to those skilled in the art. 
In a desired reaction step of the processes described hereafter, hydroxy or amino groups protection and removal of the hydroxy or amino protecting groups with reactants and reagents used may be carried out according to known procedures such as those described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley and Sons, 1991). Typical hydroxy or amino protecting groups include benzyl, C2H5O(Cxe2x95x90O)xe2x80x94, CH3(Cxe2x95x90O)xe2x80x94, t-butyldimethylsilyl(TBS), benzyloxycarbonyl represented as Z and t-But-Oxe2x80x94C(xe2x80x94O) represented as t-Boc or Boc.
Reaction Scheme 1 illustrates a method for the preparation of the compound of formula (I) wherein A is phenyl, B is ethylene, W is R1axe2x88x92N wherein R1a is H or C1-4 alkyl, and R1b is C1-4 alkyl or aryl (hereinafter represented by Formula (Ia)).
Compound (Ia) may be prepared through the process comprising:
(a) coupling reaction of a compound of formula 1-1 with 4-aminophenethylalcohol wherein X is a leaving group such as halo, mesylate(OMs) or tosylate(OTs) to give a nitroaniline compound of formula 1-2;
(b) reduction of the resulting nitroaniline compound of formula 1-2 to give a diamine compound of formula 1-3;
(c) benzimidazole or imidazopyridine ring formation with the compound of formula 1-3 to give a compound of formula 1-4;
(d) hydrolysis of the compound of formula 1-4 to give a compound of formula 1-5; conversion of the hydroxy group of the compound 1-5 into a suitable leaving group such as halo, OMs or OTs to give a compound of formula 1-6;
(e) amination of the compound of formula 1-6 to give an amino compound of formula 1-7; and
(f) sulfonylurea formation with the compound of formula 1-7 to give the compound of formula (Ia). 
Each reaction step is described more specifically as follows:
(a)-(b) The coupling reaction (a) may be carried out in the absence of, or presence of a base in a reaction inert solvent or without solvent. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. Then the resulting compound of formula 1-2 may be extracted and subjected to reduction to give the compound of formula 1-3. The reduction may be carried out in the presence of a suitable reducing agent in a reaction inert solvent or without solvent. A preferred reducing agent is selected from, for example, but not limited to, LiAlH4, LiBH4, Fe, Sn or Zn. When a reducing reagent is Fe, Sn or Zn, if desired, the reaction is carried out under acidic conditions in the presence of water. Preferred reaction inert solvents include, but are not limited to, methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, 1,4-dioxane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. The reduction may also be carried out under known hydrogenation conditions in the presence of a metal catalyst under hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or acetic acid. A preferred metal catalyst is selected from, for example, but not limited to, nickel catalysts such as Raney nickel, palladium catalysts such as Pdxe2x80x94C, platinum catalysts such as PtO2, or ruthenium catalysts such as RuCl2 (Ph3P)3. Preferred reaction inert solvents include, but are not limited to, methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 150xc2x0 C., preferably in the range of 0xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(c) The compound of formula 1-3 may be cyclized to form a benzimidazole or imidazopyridine ring by any synthetic procedure applicable to structure-related compounds known to those skilled in the art (for example, see Grimmett, M. R. Imidazoles and Their Benzo Derivatives: (iii) Synthesis and Applications. In Comprehensive Heterocyclic Chemistry, Kevin T. Potts, Eds.; Pergamon Press Ltd.: Oxford, UK, 1984; Vol.5, pp457-498., Grimmett, M. R. Imidazoles. In Comprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.3, pp77-220., Townsend L. B; Wise D. S. Bicyclo 5-6 Systems: Three Heteroatoms 2:1. In Comprehensive Heterocyclic Chemistry II, Christopher A. Ramsden, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.7, pp283-349). For example, the compound of formula 1-3 is reacted with an appropriate cyclizing reagent to give the compound of formula 1-4 in a reaction inert solvent in the presence of, or absence of a coupling reagent. If desired, this reaction may be catalyzed by an acid such as para-toluenesulfonic acid or camphersulfonic acid. Suitable cyclizing reagents include, but are not limited to, a carboxylic acid, an amino carboxylic acid, an acid anhydride (e.g., acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride and the like) a formamidine (e.g., formamidine alkylate such as formamidine acetate), an alkyl carbonyl halide (e.g., a cycloalkyl carbonyl halide, bicyclic or bicyclic-heterocyclic-carbonyl halide, spirocarbocyclic- or spiro-heterocyclic-carbonyl halide), an aryl or an aryl alkyl carbonyl halide (e.g., phenylacethyl halide), an heteroaryl carboxylic acid (e.g., a piperidinyl carboxylic acid compound), trialkyl orthoformate (e.g., triethyl orthoformate), and the like. Suitable reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran (THF), dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Suitable coupling reagents are those typically used in peptide synthesis including, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphorylazide (DPPA), or the like. The reaction may be carried out at a temperature in the range from of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a few days, preferably from 30 minutes to 48 hours, however shorter or longer reaction times, if necessary, can be employed.
(d) The hydrolysis of the compound of formula 1-4 may be carried out by conventional procedures. The hydrolysis may be carried out by treatment with base. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or halide, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate or lithium iodide, in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, water, methanol, ethanol, isopropanol, tetrahyrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(e)-(f) Step (e) and step (f) may be carried out under conditions known to those skilled in the art. For example, the hydroxy group of the compound of formula 1-5 may be converted to the halogen group using a halogenating agent in the presence or absence of a reaction inert solvent. Preferred halogenating agents include, but are not limited to, thionyl chloride, oxalyl chloride, para-toluenesulfonyl chloride, methanesulfonyl chloride, hydrogen halide such as hydrogen chloride or hydrogen bromide, phosphorus tri-halide such as phosphorus trichloride or phosphorus tribromide, phosphorus penta-halide such as phosphorus pentachloride, N-halo-succinimide such as N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS), phosphorus oxychloride, trimethylsilyl halide such as trimethylsilyl chloride or trimethylsilyl bromide, phosphorus reagents such as triphenyl phosphine, tributyl phosphine or triphenylphosphite in the presence of halogen source such as carbon tetrachloride, carbon tetrabromide, bromine, iodine, NBS or NCS. Preferred reaction inert solvents include, but are not limited to, tetrahyrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, carbon tetrabromide or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. Alternatively, a hydroxy group of the compound of formula 1-5 may be converted to the sulfonate group using a sulfonating agent in the presence of, or absence of a base. Preferred sulfonating agents include, but are not limited to, para-toluenesulfonyl chloride, para-toluenesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or the like in the presence of, or absence of a reaction-inert solvent. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxidie, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. Then, the resulting compound of formula 1-6 may be subjected to the amination to give the compound of formula 1-7. For example, the compound of formula 1-6 is reacted with R1axe2x80x94NH2 wherein R1a is as defined herein before. The reactants may be heated together in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Preferably, the reaction conducted in the presence of base. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(g) The compound of formula 1-7 may be treated with Zxe2x80x94SO2N(R2)C(xe2x95x90O)Oxe2x80x94R1b, wherein R1b is aryl or C1-4 alkyl, or Zxe2x80x94SO2NCO to give the compound of formula (Ia). The reaction may be carried out in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. If desired, the reaction may be carried out in the presence of base, such as triethyl amine, diisopropylethylamine, or N-methylmorphorine. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
The compound of formula 1-2 may also be prepared by the Ullman reaction as shown in Scheme 1a. A compound of formula 1a-1 may be treated with a compound of formula 1a-2 in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dimethylformamide (DMF), dimethoxyethane (DME) or mixtures thereof. Preferably, the reaction is conducted in the presence of metal catalyst. A preferred metal catalyst is selected from, for example, but not limited to, copper and nickel. Preferably, the reaction is conducted in the presence of base. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. 
As shown in Scheme 1b, an intermediate compound of formula 1b-4 (1-7 wherein R1a is H) may be prepared through the process comprising:
(a) azide formation; and
(b) reduction of the resulting azide compound of formula 1b-3 to give an amine compound of the formula 1b-4. 
More specifically, the nucleophilic displacement with azide may be carried out by conventional procedures in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, dimethylformamide (DMF), dimethoxyethane (DME), hexamethylphosphoramide (HMPA) or mixtures thereof. Preferred azide agents are selected from, but are not limited to, sodium azide or lithium azide. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from several minutes to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
A compound of formula 1b-3 may also be prepared by the Mitsunobu reaction. The compound of formula 1b-2 may be treated with diphenylphosphoryl azide (DPPA) or HN3 in the presence of dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD) and phosphine reagent such as triphenylphosphine. Preferably, this reaction may be carried out in a reaction-inert solvent. Preferred reaction inert solvents include, but are not limited to, tetrahydrofuran (THF), diethyl ether, dimethylformamide (DMF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, dimethoxyethane (DME), or mixtures thereof. The reduction may be carried out in the presence of a suitable reducing agent such as lithium aluminum hydride, sodium borohydride, triethyl phosphite, triphenylphosphine, zinc, dibutyl tinhydride or diboran in a reaction inert solvent selected form, but not limited to, THF, diethyl ether, methanol, ethanol. If desired, the reaction may be carried out under acidic conditions in the presence of hydrochloric acid or acetic acid. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
The reduction may also be carried out under known hydrogenation conditions in the presence of a metal catalyst such as Lindlar catalysts, Raney nickel catalysts, palladium catalysts or platinum catalysts (preferably Lindlar catalysts, palladium catalysts or platinum catalysts). This reaction may be carried out under hydrogen atmosphere in a reaction inert solvent such as methanol, ethanol, ethyl acetate or THF. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
As shown in Scheme 1c, an intermediate compound of formula 1c-5(1b-4) may also be prepared through the process comprising:
(a) coupling reaction of a compound of formula 1c-1(1-1), wherein X is a leaving group such as halo, mesylate and tosylate, with a 4-aminophenylacetonitrile to give a nitroaniline compound of formula 1c-2;
(b) chemoselective reduction of the resulting nitroaniline compound of formula 1c-2 to give a diamine compound of formula 1c-3;
(c) benzimidazole or imidazopyridine ring formation with the compound of formula 1c-3 to give a compound of formula 1c-4; and
(d) reduction of the resulting compound of formula 1c-4 to give an amine compound of the formula 1c-5(1b-4). 
Each reaction step is described more specifically as follows.
(a)-(b) The coupling reaction (a) may be carried out in the absence of, or presence of a base in a reaction inert solvent or without solvent. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
Then the resulting compound of formula 1c-2 may be extracted and subjected to reduction to give the compound of formula 1c-3. The reduction may be carried out in the presence of a reducing agent in a reaction inert solvent or without solvent. A preferred reducing agent is selected from, for example, but not limited to, Fe, Sn or Zn. If desired, the reaction is carried out under acidic conditions in the presence of water. Preferred reaction inert solvents include, but are not limited to, methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, 1,4-dioxane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(c) The compound of formula 1c-3 may be cyclized to form a benzimidazole or imidazopyridine ring by any synthetic procedure applicable to structure-related compounds known to those skilled in the art (for example, see Grimmett, M. R. Imidazoles and Their Benzo Derivatives: (iii) Synthesis and Applications. In Comprehensive Heterocyclic Chemistry, Kevin T. Potts, Eds.; Pergamon Press Ltd.: Oxford, UK, 1984; Vol.5, pp457-498., Grimmett, M. R. Imidazoles. In Comprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.3, pp77-220., Townsend L. B; Wise D. S. Bicyclo 5-6 Systems: Three Heteroatoms 2:1. In Comprehensive Heterocyclic Chemistry II, Christopher A. Ramsden, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.7, pp283-349). For example, the compound of formula 1c-3 is reacted with an appropriate cyclizing reagent to give the compound of formula 1c-4 in a reaction inert solvent in the presence of, or absence of a coupling reagent. If desired, this reaction may be catalyzed by an acid such as para-toluenesulfonic acid or camphersulfonic acid. Suitable cyclizing reagents include, but are not limited to, a carboxylic acid, an amino carboxylic acid, an acid anhydride (e.g., acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride and the like) a formamidine (e.g., formamidine alkylate such as formamidine acetate), an alkyl carbonyl halide (e.g., a cycloalkyl carbonyl halide, bicyclic or bicyclic-heterocyclic-carbonyl halide, spirocarbocyclic- or spiro-heterocyclic-carbonyl halide), an aryl or an aryl alkyl carbonyl halide (e.g., phenylacethyl halide), an heteroaryl carboxylic acid (e.g., a piperidinyl carboxylic acid compound), carbon disulfide, trialkyl orthoformate (e.g., triethyl orthoformate), and the like. Suitable reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran (THF), dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Suitable coupling reagents are those typically used in peptide synthesis including, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphorylazide (DPPA), or the like. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a few days, preferably from 30 minutes to 48 hours, however shorter or longer reaction times, if necessary, can be employed.
The reduction of the compound of formula 1c-4 may be carried out in the presence of a suitable reducing agent such as diboran, boran-methyl sulfide complex, or lithium aluminum hydride in a reaction inert solvent selected form, but not limited to, THF or diethyl ether. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
The reduction of the compound of formula 1c-4 may also be carried out under known hydrogenation conditions such as in the presence of a metal catalyst such as Raney nickel catalysts, palladium catalysts or platinum catalysts under hydrogen atmosphere. This reaction may be carried out in a reaction inert solvent such as methanol, ethanol, chloroform or THF in the presence or absence of hydrogen chloride. If necessary, this reduction may be carried out under the adequate pressure in the range from about 0.5 to 10 kg/cm2, preferably in the range from 1 to 6 kg/cm2. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
The compound of formula (Ia) may also be prepared from the compound of formula 1d-1(1-7) through a carbamate compound of formula 1d-2, as depicted in Scheme 1d. 
The compound of formula 1d-1(1-7) may be treated with the carbonating agents (R1d is aryl or C1-4 alkyl) such as alkyl or aryl haloformate, dialkyl or diary dicarbonate or alkyl or aryl hydrogen dicarbonate in the presence or absence of a base. Suitable bases include, for example, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from several minutes to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
The resulting carbamate compound of formula 1d-2 may reacted with the sulfonamide compound in the presence of a base such as listed above in a reaction inert solvent as listed above (preferably DMF). Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C. , preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
As shown in Scheme 1e, an intermediate compound of formula 1e-5 (1b-4) may also be prepared through the process comprising:
(a) coupling reaction of a compound of formula 1e-1 (1-1), wherein X is a leaving group such as halo, mesylate, tosylate, and triflate with a protected 4-aminophenylethylamine to give a nitroaniline compound of formula 1e-2;
(b) reduction of the resulting nitroaniline compound of formula 1e-2 to give a diamine compound of formula 1e-3;
(c) benzimidazole or imidazopyridine ring formation with the compound of formula 1e-3 to give a compound of formula 1e-4; and
(d) deprotection of the resulting compound of formula 1e-4 to give an amine compound of the formula 1e-5 (1b-4). 
Each reaction step is described more specifically as follows.
(a)-(b) The coupling reaction (a) may be carried out in the absence of, or presence of a base in a reaction inert solvent. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine in the presence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. Then the resulting compound of formula 1e-2 may be extracted and subjected to reduction to give the compound of formula 1e-3. The reduction may be carried out in the presence of a reducing agent in a reaction inert solvent. A preferred reducing agent is selected from, for example, but not limited to, Fe, Sn or Zn. If desired, the reaction is carried out under acidic conditions in the presence of water. Preferred reaction inert solvents include, but are not limited to, methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, 1,4-dioxane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. The reduction may also be carried out under known hydrogenation conditions in the presence of a metal catalyst under hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or acetic acid. A preferred metal catalyst is selected from, for example, but not limited to, nickel catalysts such as Raney nickel, palladium catalysts such as Pdxe2x80x94C, platinum catalysts such as PtO2, or ruthenium catalysts such as RuCl2xe2x80x94(Ph3P)3. Preferred reaction inert solvents include, but are not limited to, methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 150xc2x0 C., preferably in the range of 0xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(c) The compound of formula 1e-3 may be cyclized to form a benzimidazole or imidazopyridine ring by any synthetic procedure applicable to structure-related compounds known to those skilled in the art (for example, see Grimmett, M. R. Imidazoles and Their Benzo Derivatives: (iii) Synthesis and Applications. In Comprehensive Heterocyclic Chemistry, Kevin T. Potts, Eds.; Pergamon Press Ltd.: Oxford, UK, 1984; Vol.5, pp457-498., Grimmett, M. R. Imidazoles. In Comprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.3, pp77-220., Townsend L. B; Wise D. S. Bicyclo 5-6 Systems: Three Heteroatoms 2:1. In Comprehensive Heterocyclic Chemistry II, Christopher A. Ramsden, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.7, pp283-349). For example, the compound of formula 1e-3 is reacted with an appropriate cyclizing reagent to give the compound of formula 1e-4 in a reaction inert solvent in the presence of, or absence of a coupling reagent. If desired, this reaction may be catalyzed by an acid such as para-toluenesulfonic acid or camphersulfonic acid. Suitable cyclizing reagents include, but are not limited to, a carboxylic acid, an amino carboxylic acid, an acid anhydride (e.g., acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride and the like) a formamidine (e.g., formamidine alkylate such as formamidine acetate), an alkyl carbonyl halide (e.g., a cycloalkyl carbonyl halide, bicyclic or bicyclic-heterocyclic-carbonyl halide, spirocarbocyclic- or spiro-heterocyclic-carbonyl halide), an aryl or an aryl alkyl carbonyl halide (e.g., phenylacethyl halide), an heteroaryl carboxylic acid (e.g., a piperidinyl carboxylic acid compound), carbon disulfide, trialkyl orthoformate (e.g., triethyl orthoformate), and the like. Suitable reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran (THF), dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Suitable coupling reagents are those typically used in peptide synthesis including, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphorylazide (DPPA), or the like. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a few days, preferably from 30 minutes to 48 hours, however shorter or longer reaction times, if necessary, can be employed.
(d) The deprotection of the compound of formula 1e-4 may be carried out according to known procedures such as those described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley and Sons, 1991). Typical amino protecting groups include benzyl represented as Bn, benzyloxycarbonyl represented as Cbz or Z and t-But-Oxe2x80x94C(xe2x95x90O)xe2x80x94 represented as t-Boc or Boc. In the case of Bn or Z protection, the removal of the amino protecting groups may be carried out under, for example, but not limited to, known hydrogenolysis conditions in the presence of a metal catalyst under hydrogen atmosphere or in the presence of hydrogen sources such as formic acid or ammonium formate in a reaction inert solvent. If desired, the reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or acetic acid. A preferred metal catalyst is selected from, for example, but not limited to, palladium catalysts such as Pdxe2x80x94C. Preferred reaction inert solvents include, but are not limited to, methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 150xc2x0 C., preferably in the range of 0xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. In the case of Boc protection, the removal of the amino protecting groups may be carried out under, for example, but not limited to, known acid hydrolysis conditions in a reaction inert solvent or without solvent. If desired, the reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or trifluoroacetic acid with a reaction inert scavenger of t-butyl cations. Preferred reaction inert scavenger of t-butyl cations include, but are not limited to, benzene, thiophenol, anisole, thioanisole, thiocresole, cresole, or dimethyl sulfide. Preferred reaction inert solvents include, but are not limited to, methanol, ethanol, ethyl acetate, dioxane or mixtures thereof. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 150xc2x0 C., preferably in the range of 0xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 1f illustrates a method for the preparation of the compound of formula (I) wherein W is R1axe2x80x94N wherein R1a is H or C1-4 alkyl, and R1b is C1-4 alkyl or aryl (hereinafter represented by Formula (If)).
Compound (If) may be prepared through the process comprising:
(a) coupling reaction of a compound of formula 1f-1 with a compound of formula 1f-0 wherein X is a leaving group such as halo, mesylate(OMs) or tosylate(OTs) to give a nitroaniline compound of formula 1f-2;
(b) reduction of the resulting nitroaniline compound of formula 1f-2 to give a diamine compound of formula 1f-3;
(c) benzimidazole or imidazopyridine ring formation with the compound of formula 1f-3 to give a compound of formula 1f-4;
(d) hydrolysis of the compound of formula 1f-4 to give a compound of formula 1f-5; conversion of the hydroxy group of the compound 1f-5 into a suitable leaving group such as halo, OMs or OTs to give a compound of formula 1f-6;
(e) amination of the compound of formula 1f-6 to give an amino compound of formula 1f-7; and
(f) sulfonylurea formation with the compound of formula 1f-7 to give the compound of formula (If). 
Each reaction step is described more specifically as follows:
(a)-(b) The coupling reaction (a) may be carried out in the absence of, or presence of a base in a reaction inert solvent or without solvent. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. Then the resulting compound of formula 1f-2 may be extracted and subjected to reduction to give the compound of formula 1f-3. The reduction may be carried out in the presence of a suitable reducing agent in a reaction inert solvent or without solvent. A preferred reducing agent is selected from, for example, but not limited to, LiAlH4, LiBH4, Fe, Sn or Zn. When a reducing reagent is Fe, Sn or Zn, if desired, the reaction is carried out under acidic conditions in the presence of water. Preferred reaction inert solvents include, but are not limited to, methanol, ethanol, diglyme, benzene, toluene, xylene, o-dichlorobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, 1,4-dioxane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. The reduction may also be carried out under known hydrogenation conditions in the presence of a metal catalyst under hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction is carried out under acidic conditions, for example, in the presence of hydrochloric acid or acetic acid. A preferred metal catalyst is selected from, for example, but not limited to, nickel catalysts such as Raney nickel, palladium catalysts such as Pdxe2x80x94C, platinum catalysts such as PtO2, or ruthenium catalysts such as RuCl2 (Ph3P)3. Preferred reaction inert solvents include, but are not limited to, methanol, ethanol, ethyl acetate, THF or mixtures thereof. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 150xc2x0 C., preferably in the range of 0xc2x0 C. to 100xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(c) The compound of formula 1f-3 may be cyclized to form a benzimidazole or imidazopyridine ring by any synthetic procedure applicable to structure-related compounds known to those skilled in the art (for example, see Grimmett, M. R. Imidazoles and Their Benzo Derivatives: (iii) Synthesis and Applications. In Comprehensive Heterocyclic Chemistry, Kevin T. Potts, Eds.; Pergamon Press Ltd.: Oxford, UK, 1984; Vol.5, pp457-498., Grimmett, M. R. Imidazoles. In Comprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.3, pp77-220., Townsend L. B; Wise D. S. Bicyclo 5-6 Systems: Three Heteroatoms 2:1. In Comprehensive Heterocyclic Chemistry II, Christopher A. Ramsden, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.7, pp283-349). For example, the compound of formula 1f-3 is reacted with an appropriate cyclizing reagent to give the compound of formula 1f-4 in a reaction inert solvent in the presence of, or absence of a coupling reagent. If desired, this reaction may be catalyzed by an acid such as para-toluenesulfonic acid or camphersulfonic acid. Suitable cyclizing reagents include, but are not limited to, a carboxylic acid, an amino carboxylic acid, an acid anhydride (e.g., acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride and the like) a formamidine (e.g., formamidine alkylate such as formamidine acetate), an alkyl carbonyl halide (e.g., a cycloalkyl carbonyl halide, bicyclic or bicyclic-heterocyclic-carbonyl halide, spirocarbocyclic- or spiro-heterocyclic-carbonyl halide), an aryl or an aryl alkyl carbonyl halide (e.g., phenylacethyl halide), an heteroaryl carboxylic acid (e.g., a piperidinyl carboxylic acid compound), trialkyl orthoformate (e.g., triethyl orthoformate), and the like. Suitable reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran (THF), dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Suitable coupling reagents are those typically used in peptide synthesis including, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphorylazide (DPPA), or the like. The reaction may be carried out at a temperature in the range from of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a few days, preferably from 30 minutes to 48 hours, however shorter or longer reaction times, if necessary, can be employed.
(d) The hydrolysis of the compound of formula 1f-4 may be carried out by conventional procedures. The hydrolysis may be carried out by treatment with base. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or halide, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate or lithium iodide, in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, water, methanol, ethanol, isopropanol, tetrahyrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(e)-(f) Step (e) and step (f) may be carried out under conditions known to those skilled in the art. For example, the hydroxy group of the compound of formula 1f-5 may be converted to the halogen group using a halogenating agent in the presence or absence of a reaction inert solvent. Preferred halogenating agents include, but are not limited to, thionyl chloride, oxalyl chloride, para-toluenesulfonyl chloride, methanesulfonyl chloride, hydrogen halide such as hydrogen chloride or hydrogen bromide, phosphorus tri-halide such as phosphorus trichloride or phosphorus tribromide, phosphorus penta-halide such as phosphorus pentachloride, N-halo-succinimide such as N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS), phosphorus oxychloride, trimethylsilyl halide such as trimethylsilyl chloride or trimethylsilyl bromide, phosphorus reagents such as triphenyl phosphine, tributyl phosphine or triphenylphosphite in the presence of halogen source such as carbon tetrachloride, carbon tetrabromide, bromine, iodine, NBS or NCS. Preferred reaction inert solvents include, but are not limited to, tetrahyrofuran (THF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, carbon tetrachloride, carbon tetrabromide or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. Alternatively, a hydroxy group of the compound of formula 1f-5 may be converted to the sulfonate group using a sulfonating agent in the presence of, or absence of a base. Preferred sulfonating agents include, but are not limited to, para-toluenesulfonyl chloride, para-toluenesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, or the like in the presence of, or absence of a reaction-inert solvent. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, potassium fluoride, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. Then, the resulting compound of formula 1f-6 may be subjected to the amination to give the compound of formula 1f-7. For example, the compound of formula 1f-6 is reacted with R1axe2x80x94NH2 wherein R1a is as defined herein before. The reactants may be heated together in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Preferably, the reaction conducted in the presence of base. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(g) The compound of formula 1f-7 may be treated with Zxe2x80x94SO2N(R2)C(xe2x95x90O)Oxe2x80x94R1b, wherein R1b is aryl or C1-4 alkyl, or Zxe2x80x94SO2NCO to give the compound of formula (If). The reaction may be carried out in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. If desired, the reaction may be carried out in the presence of base, such as triethyl amine, diisopropylethylamine, or N-methylmorphorine. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
As described in scheme 2, the compound of formula (I), wherein A is phenyl, B is ethylene and W is NH (hereinafter represented by Formula (Ib)), may be prepared through the process comprising:
(a) coupling reaction of a compound of formula 2-1(1-1), wherein X is a leaving group such as halo, mesylate or tosylate with 2-(4-aminophenyl)propionic acid or ester (2-2) (when using ester derivative of 2-2, followed by hydrolysis) to give a nitroaniline compound of formula 2-3;
(b) Curutius rearrangement of the compound of formula 2-3 followed by treating with an alcohol or a phenol to give a carbamate compound of formula 2-5;
(c) sulfonylurea formation with compound of formula 2-5 to give a compound of formula 2-6;
(d) reduction of the resulting nitroaniline compound of formula 2-6 to give a diamine compound of formula 2-7; and
(e) benzimidazole or imidazopyridine ring formation with the compound of formula 2-7 to give a compound of formula (Ib);
Each reaction step is described more specifically as follows.
(a) The compound of formula 2-3 may be prepared from the compound of 2-1(1-1) according to the similar procedure to that of described in Scheme 1.
(b) Curutius rearrangement of the compound of formula 2-3 may be carried out by conventional procedures. In a typical procedure, the rearrangement is carried out by treatment with DPPA in the presence of a base in a reaction inert solvent. Suitable bases include, for example, an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, tetrahyrofuran (THF), 1,4-dioxane, or mixtures thereof. Reaction temperatures are generally in the range of 0 to 250xc2x0 C., preferably in the range of 25xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
The obtained isocyanate 2-4 may be treated with an alcohol or a phenol to give the compound of formula 2-5. Reaction temperatures are generally in the range of 0 to 250xc2x0 C., preferably in the range of 25xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from several minutes to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(c) Treatment of the obtained carbamate compound of formula 2-5 with sulfonamide in the presence or absence of a base may give the compound of formula 2-6. Suitable bases include, for example, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, sodium hydride or potassium hydride in the presence or absence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(d) and (e) The reduction of the compound 2-6 and the following ring formation may be carried out in an analogous manner to those of described in Scheme 1 to give the compound of formula (Ib). 
As shown in Scheme 2a, an intermediate compound of formula 2a-3 (2-7) may also be prepared through the procedure comprising
(a) reduction of the above obtained compound 2a-1 (2-5) to give a diamine compound of formula 2a-2; and
(b) sulfonylurea formation of the compound of formula 2a-2 may give a compound of formula 2a-3 (2-7).
The reduction of the compound of formula 2a-1 (2-5), and sulfonylurea formation with the obtained compound of formula 2a-2 may be carried out by the same procedure as described in scheme 1 and 1d.
As shown in scheme 2a, a carbamate compound of formula 2a-4 may be prepared from the compound of formula 2a-2 by the cyclization according to the same procedure as described in Scheme 1. 
Alternatively, an intermediate compound of formula 2b-5(2-5) may also be prepared from a carboxylic acid compound of formula 2b-1(2-3) by the methods illustrated in Scheme 2b. Path A in Scheme 2b illustrates a preparation procedure for a compound of formula 2b-5 (2-5) according to the Hoffman rearrangement (e.g., Wallis; Lane Org React. 1946, 3, 267-306). The amide compound of formula 2b-2 may be prepared by known methods (e.g., Org. Syn. Coll Vol 4, 513 (1963)). Hoffman rearrangement of the obtained carboxamide compound of formula 2b-2 may be carried out under the known conditions followed by treatment with an alcohol or a phenol under the same conditions described in Scheme 2 to afford the compound of formula 2b-5 (2-5). Path B in Scheme 2b illustrates a preparation procedure for the compound of formula 2b-5 (2-5) according to Lossen rearrangement (e.g., Bauer; Exner Angew. Chem. Int Ed. Engl. 1974, 13, 376-384). The O-acyl hydroxamic acid compound of formula 2b-3 may be prepared by known methods (e.g., Miller, Marvin J.; Mattingly, Phillip G.; Morrison, Marjorie A.; Kerwin, James F., J.Amer.Chem.Soc., 1980, 102, 7026-7032). The carboxylic acid compound of formula 2b-1 (2-3) may be treated with hydroxamic acid derivative, usually O-acyl hydroxamic acid, in the presence of coupling agent such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphorylazide (DPPA), or the like. This reaction may be carried out at from about 0xc2x0 C. to the reflux temperature of the reaction mixture, preferably from about room temperature to the reflux temperature for about 1 minute to about 120 hours, preferably for from about 10 minutes to about 72 hours. Lossen rearrangement of the obtained O-acyl hydroxamic acid compound of formula 2b-3 may be carried out under the known conditions followed by treatment with an alcohol or a phenol under the same conditions described in Scheme 2 to afford the compound of formula 2b-5(2-5). 
The compound of formula (Ia) may be prepared from the compound of formula (Ia1), wherein R2 is H, by methods known to those skilled in the art as depicted in Scheme 3. The compound of formula (Ia1) may be treated with appropriate alkyl halides, R2-halo in the presence of a base such as lithium diisopropyl amide (LDA), sodium hydride (NaH) or potassium t-butoxide in a reaction inert solvent such as THF or DMF at about 0xc2x0 C. to 80xc2x0 C. for 20 minutes to 24 hours. 
As depicted in Scheme 4, a carbamate compound of formula 4-2 may be prepared from a compound of formula 4-1(1-5) according to the same conditions described in Scheme 1. More specifically, the compound of formula 4-1 may be treated with Zxe2x80x94SO2N(R2)C(xe2x95x90O)Oxe2x80x94 R1b wherein R1b is aryl or C1-4 alkyl or Zxe2x80x94SO2NCO to give the compound of formula (4-2). The reaction may be carried out in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. If desired, the reaction may be carried out in the presence of base, such as triethyl amine, diisopropylethylamine, or N-methylmorphorine. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. 
As shown in Scheme 5, the compound of formula (I), wherein A is phenyl, B is ethylene and W is Nxe2x80x94OR7 (hereinafter represented by Formula (Id)) may be prepared through the process comprising:
(a) Mitsunobu reaction of a compound of formula 5-1 (1-5) to give a compound of formula 5-2;
(b) cleavage of the protecting group of the compound of formula 5-2 to give a hydroxyamine compound of formula 5-3; and
(c) sulfonylurea formation with the compound of formula 5-3 to give a compound of formula (Id).
As shown in Scheme 4a, the compound of formula 4a-3 (4-2) may also be prepared by reacting a compound of formula 4a-1 with a substituted benzene compound of formula 4a-2 to give a 1-phenylbenzimidazole compound of formula 4a-3 (4-2); The compounds of formula 4a-1 may be synthesized by any of the known methods. The group G19 of the compounds of formula 4a-2 is a selected from a suitable displaceable group, for example, fluoro, chloro, bromo, iodo, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, or boronic acid group. 
The coupling reaction may be carried out in the presence of a base in a reaction inert solvent. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, acetonitrile, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to several weeks, preferably from 20 minutes to 1 week, however shorter or longer reaction times, if necessary, can be employed. Conveniently, the compound of formula 4a-1 may be reacted with the compound of formula 4a-2 in the presence of a suitable catalyst to form the compound of formula 4a-3 (4-2) by any synthetic procedure applicable to structure-related compounds known to those skilled in the literature (e.g., Lam, P. Y. S.; Clark, C. G.; Saubern, S; Adams, J; Winters, M. P.; Chan, D. M. T.; Combs, A., Tetrahedron Lett., 1998, 39, 2941-2944., Kiyomori, A.; Marcoux, J.; Buchwald, S. L., Tetrahedron Left., 1999, 40, 2657-2660., Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong, P.; Clark, C. G., J. Am. Chem. Soc., 2000, 122,7600-7601., Collman, J. P.; Zhong, M., Org. Lett., 2000, 2, 1233-1236.). Preferred reaction catalyst is selected from, for example, but not limited to, tetrakis(triphenylphosphine)-palladium, bis(triphenylphosphine)palladium(II) chloride, copper(I), copper(I) acetate, copper(I) bromide, copper(I) chloride, copper(I) iodide, copper(I) oxide, copper(II) trifluoromethanesulfonate, copper(II) acetate, copper(II) bromide, copper(II) chloride, copper(II) iodide, copper(II) oxide, or copper(II) trifluoromethanesulfonate. 
Each reaction step is described more specifically as follows.
(a) The compound of formula 5-2 may be prepared by the Mitsunobu reaction. The compound of formula 5-1 may be treated with HN(OR7)G1 wherein G1 is H or a protecting group, preferably, G1 is a suitable protecting group, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Z), phenylsulfonyl, p-toluenesulfonyl, or the like, and R7 is an alkyl (e.g., methyl or ethyl) or G2 (G2 is a suitable protecting group, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Z), phenylsulfonyl, p-toluenesulfonyl, trimethylsilyl, t-butyldimethylsilyl, or the like)). For example, the compound of formula 5-1 is reacted with [N,O-Bis-protectedhydroxylamine] (e.g., Baillie, L. C.; Batsanov, A.; Bearder, J. R.; Whiting, D. A. J. Chem. Soc. Perkin Trans. 1, 1998, 20, 3471.) in the presence of dialkyl azodicarboxylate such as diethyl azodicarboxylate (DEAD) and phosphine reagent such as triphenylphosphine. Preferably, this reaction may be carried out in a reaction-inert solvent. Preferred reaction inert solvents include, but are not limited to, tetrahydrofuran (THF), diethyl ether, dimethylformamide (DMF), benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, dimethoxyethane (DME), or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(b) Cleavage of the protecting group may be carried out by a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for the Hydroxy Group and the Amino Groupxe2x80x9d, in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 10-142, 309-405).
(c) sulfonylurea formation may be carried out according to the conditions illustrated in Scheme 1. Specifically, the compound of formula 5-3 may be treated with Zxe2x80x94SO2N(R2)C(xe2x95x90O)Oxe2x80x94R1b wherein R1b is aryl or C1-4,alkyl, or Zxe2x80x94SO2NCO to give the compound of formula (Id). The reaction may be carried out in the absence or presence of a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, or mixtures thereof. If desired, the reaction may be carried out in the presence of base, such as triethyl amine, diisopropylethylamine, or N-methylmorphorine. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
Reaction Scheme 6 illustrates a method for the preparation of the compound of formula (Ia), wherein at least one of Y1, Y2, Y3 and Y4 is Cxe2x80x94CONH2, A is phenyl, B is ethylene and W is R1axe2x80x94N (R1a is H or C1-4 alkyl) (hereinafter represented by Formula (Ia2)), and that of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is Cxe2x80x94CO2H, A is phenyl and B is ethylene and W is R1axe2x80x94N (R1a is H or C1-4 alkyl) (hereinafter represented by Formula (Ia3)). Compound (Ia3) may be prepared through the process comprising:
(a) hydrolysis of a compound of formula 6-1 to give a compound of formula 6-2;
(b) conversion of the hydroxy group of the compound 6-2 into the leaving group such as halo, mesylate and tosylate to give a compound of formula 6-3;
(c) azide formation;
(d) reduction of the resulting azide compound followed by sulfonylurea formation to give the compound of formula (Ia2); and
(e) hydrolysis of the compound of formula (Ia2) to give the compound of formula (Ia3);
Each reaction step is described more specifically as follows:
(a) Intermediate 6-1 may be prepared by the methods illustrated in Scheme 1. The hydrolysis of the compound of formula 6-1 may be carried out by conventional procedures. The hydrolysis may be carried out by treatment with a peroxide such as hydrogen peroxide in the presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide or ammonium hydroxide in a suitable solvent such as aqueous methanol, dimethylsulfoxide and tetrahydrofuran. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. The hydrolysis may also be carried out by treatment with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an acid such as sulfuric acid in a suitable solvent such as aqueous methanol, aqueous ethanol, t-butanol or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from several minutes to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(b) (c) and (d) Step (b), (c) and step (d) may be carried out according to the conditions illustrated in Scheme 1 and 1b.
(e) The hydrolysis of the compound of formula (Ia2) may be carried out by conventional procedures. The hydrolysis may be carried out by treatment with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an acid such as sulfuric acid or phosphoric acid in a suitable solvent such as aqueous methanol, ethanol ethylene glycol, water, tetrahydrofuran or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. 
Reaction Scheme 7 illustrates an alternative method for the preparation of the compound of formula (Ia2). A compound of formula (Ia4) may be prepared by the methods illustrated in Scheme 1. Hydrolysis of the compound of formula (Ia4) may be carried out by treatment with a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide or ammonium hydroxide in a suitable solvent such as aqueous methanol, dimethylsulfoxide and tetrahydrofuran. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. The hydrolysis may also be carried out by treatment with a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or an acid such as sulfuric acid in a suitable solvent such as aqueous methanol, aqueous ethanol, t-butanol or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. 
Reaction Scheme 8 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is Cxe2x80x94OG1 wherein G1 is defined before, A is phenyl, B is ethylene and W is R1axe2x80x94N (R1a is H or C1-4 alkyl), (hereinafter represented by Formula (Ia5)) and that of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is Cxe2x80x94OH, A is phenyl B is ethylene and W is R1axe2x80x94N (R1a is H or C1-4 alkyl), (hereinafter represented by Formula (Ia6)). Compound (Ia6) may be prepared through the process comprising:
(a) dealkylation of a compound of formula 8-1 to give a compound of formula 8-2;
(b) protection of the hydroxy group of the compound 8-2 to give a compound of formula 8-3;
(c) preparation of the compound of formula (Ia5); and
(d) cleavage of the protecting group of the compound of formula (Ia5) to give the compound of formula (Ia6). 
Each reaction step is described more specifically as follows.
(a) Intermediate 8-1, wherein R8 is C1-C4alkyl, may be prepared by the methods illustrated in Scheme 1. dealkylation of the compound of formula 8-1 may be carried out a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection of Phenolsxe2x80x9d, in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 1-43-174). For example, the compound of formula 8-1 may be treated with a proton and/or Lewis acid such as hydrogen bromide or aluminum chloride in a suitable solvent such as water, acetic acid or dichloromethane. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. The reaction may also carried out in the presence of a thioalkoxide such as sodium thiomethoxide, lithium thiomethoxide, sodium thioethoxide in the presence or absence of a reaction inert solvent such as DMSO, DMF or HMPA. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(b) Protection of the compound of formula 8-2 may be carried out according to a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection of Phenolsxe2x80x9d, in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 143-174).
(c) Preparation of the compound of formula (Ia5) may be carried out according to the conditions illustrated in Scheme 1 and 1b.
(d) Cleavage of the protecting group may be carried out by a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection of Phenolsxe2x80x9d, in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 143-174).
As depicted in Scheme 9, the compound of formula (la), wherein at least one of Y1, Y2, Y3 and Y4 is Cxe2x80x94SO2NH2, A is phenyl, B is ethylene and W is R1axe2x80x94N (R1a is H or C1-4alkyl), (hereinafter represented by Formula (Ia8)) may be prepared from the compound of formula (Ia), wherein at least one of Y1, Y2, Y3 and Y4 is Cxe2x80x94SO2NHtBu, A is phenyl, B is ethylene and W is R1axe2x80x94N (R1a is H or C1-4alkyl), (hereinafter represented by Formula (Ia7)). The compound of formula (Ia7) may be prepared by the methods illustrated in Scheme 1 and 1b. Cleavage of the protecting group may be carried out by a number of standard procedures known to those skilled in the art (e.g., Quan, Mimi L.; Ellis, Christopher D.; Liauw, Ann Y.; Alexander, Richard S.; Knabb, Robert M., et al., J. Med. Chem., 1999, 42, 2760-2773). 
Reaction Scheme 10 illustrates a method for the preparation of the compound formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is Cxe2x80x94NHSO2R10, A is phenyl, B is ethylene, R10 is C1-C4 alkyl, W is R1axe2x80x94N (R1a is H or C1-4alkyl), (hereinafter represented by Formula (Ia9)). 
Compound (Ia9) may be prepared through the process comprising:
(a) reduction of a compound of formula 10-1 to give a compound of formula 10-2;
(b) sulfonylation of the amino group of the compound 10-2 to give a compound of formula 10-3; and
(c) formation of a compound of formula (Ia9);
Each reaction step is described more specifically as follows.
(a) The intermediate 10-1 may be prepared by the methods illustrated in Scheme 1. Reduction of nitro group may be carried out according to the conditions illustrated in Scheme 1.
(b) Sulfonylation of the amino group of the compound 10-2 may be carried out by a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for the Hydroxy Group and the Amino Groupxe2x80x9d, in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 117-118, 379-384).
(c) Formation of the sulfonylurea compound of formula (Ia9) may be carried out according to the conditions illustrated in Scheme 1 and 1b.
Reaction Scheme 11 illustrates a method for the preparation of the compound of formula (Ia) wherein at least one of Y1, Y2, Y3 and Y4 is Cxe2x80x94NHC(xe2x95x90O)N(R3)(R4), A is phenyl, B is ethylene and W is R1axe2x80x94N (R1a is H or C1-4alkyl), (hereinafter represented by Formula (Ia10)). Compound (Ia10) may be prepared through the process comprising:
(a) urea formation with a compound of formula 11-1(10-2) to give a compound of formula 11-2; and
(b) formation of a compound of formula (Ia10);
Each reaction step is described more specifically as follows.
(a) The intermediate 11-1(10-2) as obtained in Scheme 10, may be treated with an isocyanate or cyanic acid (usually its salts) according to known procedures (e.g., Satchell and Satchell, Chem. Soc. Rev., 1975, 4, 231-250). More specifically, this reaction may be carried out in a suitable reaction inert solvent such as dichloromethane, THF, benzene or toluene. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed.
(c) Formation of the sulfonylurea compound of formula (Ia10) may be carried out according to the conditions illustrated in Scheme 1 and 1b. 
Intermediate compound 12-2 may be prepared by the methods illustrated in Scheme 12. Intermediate 12-1 may be prepared by the methods illustrated in Scheme 1 and Scheme 1b. The reduction may be carried out under known hydrogenation conditions such as in the presence of a metal catalyst such as palladium catalysts or platinum catalysts in a reaction inert solvent such as methanol, ethanol, ethyl acetate or THF. If desired, the reaction is carried out under acidic conditions in the presence of an acid such as hydrogen chloride or acetic acid. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. 
In addition, an intermediate compound 13-2 may be prepared by the methods illustrated in Scheme 13. Intermediate 13-1 may be prepared by the methods illustrated in Scheme 1. The reduction may also be carried out by the methods illustrated in Scheme 1. 
An intermediate compound 14-3 may be prepared by the methods illustrated in Scheme 14. Intermediate 14-1 may be prepared by the methods illustrated in Scheme 1. Reduction of nitro group may be carried out according to the conditions illustrated in Scheme 1. Sulfonylation of the amino group of the compound 14-2 may be carried out by a number of standard procedures known to those skilled in the art (e.g., xe2x80x9cProtection for the Hydroxy Group and the Amino Groupxe2x80x9d, in Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, Ed., John Wiley and Sons, Inc. 1991, pp. 117-118, 379-384). 
Intermediate compounds 15-6 and 15-7 may be prepared by the methods illustrated in Scheme 15. A compound of formula 15-1 may be treated with aqueous ammonia. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from an hour to a week, preferably from 3 hours to 5 days, however shorter or longer reaction times, if necessary, can be employed. Thus, the obtained intermediate 15-2 may be treated with 1,3-diketone compound of formula 15-3, wherein L1, L2 and L3 is independently selected from, but not limited to, halo, C1-4alkyl, halo-substituted C1-4 alkyl, C1-4 alkoxy, halo-substituted C1-4 alkoxy, nitro, cyano, C1-4 alkoxy-C1-4alkyl, acetyl, C3-7 cycloalkyl, or two adjacent L1, L2 and L3 groups may be joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms may be replaced by oxygen atoms in the presence of a base such as pyridine, piperadine, imidazole, N,N-dimethylaminopyridine, CH3C(xe2x95x90O)ONa or NaH2PO4 and in the presence or absence of an acid such as acetic acid, hydrochloric aid or boric acid. Suitable reaction inert solvent includes water, dioxane, DMSO, DMF, p-toluene or ethanol. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from an hour to a month, preferably from 6 hours to 14 days, however shorter or longer reaction times, if necessary, can be employed. Compounds 15-4 and 15-5 as obtained above may be treated with halogenating agent such as POCl3, SOCl2 or Vilsmeier complex (e.g., Laue T.; Plagens A., Eds.; NAMED ORGANIC REACTIONS, Wiley and Sons: New York, 1998, pp 258-262) in the presence or absence of a suitable reaction inert solvent such as dichloromethane, benzene or DMF to give compounds of formula 15-6 and/or 15-7. Reaction temperatures are generally in the range of xe2x88x92100xc2x0 C. to 250xc2x0 C. preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a day, preferably from 20 minutes to 5 hours, however shorter or longer reaction times, if necessary, can be employed. 
Reaction Scheme 16 illustrates a method for the preparation of the compound of formula (I) wherein R1 is NH2, A is phenyl, B is ethylene and W is NH (hereinafter represented by Formula (Ia11)) and that of the compound of formula (I), wherein R1 is NHC(xe2x95x90O)R16 (R16 is C1-4 alkyl), A is phenyl, B is ethylene and W is NH (hereinafter represented by Formula (Ia12)) and that of the compound of formula (I), wherein R1 is NHS(O)2R16 (R16 is C1-4 alkyl), A is phenyl, B is ethylene and W is NH (hereinafter represented by Formula (Ia13))
Compounds (Ia11), (Ia12) and (Ia13) may be prepared through the process comprising:
(a) 2-amino-benzimidazole or 2-amino-imidazopyridine ring formation) with a compound of formula 16-1(2-7) to give the compound of formula (Ia11);
(b) carbonylation of the compound of formula (Ia11) to give the compound of formula (Ia12); and
(c) sulfonylation of the compound of formula (Ia11) to give the compound of formula (Ia13).
Each reaction step is described more specifically as follows.
(a) The compound 16-1(2-7) can be cyclized to form a benzimidazole or a imidazopyridine ring by reaction with an appropriate cyclizing agent to give the compound of formula (Ia11) in a reaction inert solvent. Suitable cyclizing agents include cyanogen halide (e.g., cyanogen bromide), cyanamide, and guanidine-carbamate. Suitable solvents include tetrahydrofuran (THF), methanol, ethanol, acetonitrile, water, dimethylformamide and the like. This reaction may be carried out at about 0xc2x0 C. to the reflux temperature of the reaction mixture, preferably at room temperature to the reflux temperature for about 1 minute to 120 hours, preferably 10 minutes to 72 hours.
(b) The compound of formula (Ia11) may be reacted with an acylating agent such as alkylcarbonyl halide, acid anhydride in the presence of a base such as triethylamine or pyridine. Suitable reaction inert solvents include THF, DMF or benzene. The reaction may be carried out at about 0xc2x0 C. to about reflux temperature for about 1 minute to 120 hours, preferably 10 minutes to 48 hours.
(c) The compound of formula (Ia11) may also be reacted with an sulfonylating agent such as alkylsulfonyl halide, sulfonic acid anhydride in the presence of a base such as triethylamine or pyridine. Suitable reaction inert solvents include dichloromethane, THF, DMF or benzene. The reaction may be carried out at about 0xc2x0 C. to about reflux temperature for about 1 minute to 120 hours, preferably 10 minutes to 48 hours. 
Reaction Scheme 17 illustrates a method for the preparation of the compound of formula (I) wherein R1 is R16NH (R16 is C1-8 alkyl), A is phenyl, B is ethylene and W is O or R1axe2x80x94N (R1a is H or C1-4alkyl) (hereinafter represented by Formula (Ia14)) and that of the compound of formula (I), wherein R1 is (R16)2N (R16 is C1-8 alkyl), A is phenyl, B is ethylene and W is O or R1axe2x80x94N (R1a is H or C1-4alkyl) (hereinafter represented by Formula (Ia15)).
Compounds (Ia14) and (Ia15) may be prepared through the process comprising:
(a) 2-amino-benzimidazole or 2-amino-imidazopyridine ring formation with a compound of formula 17-1 to give a compound of formula (Ia14); and
(b) alkylation of the compound of formula (Ia14) to give a compound of formula (Ia15).
Each reaction step is described more specifically as follows.
(a) A compound of formula 17-1 may be subjected to a reaction with an isothiocyanate compound and a subsequent desulfurization under known conditions to give the compound of formula (Ia14) (e.g., Y. Abe, H. Kayakiri, S. Satoh et al., J. Med. Chem. 1998, 41, 4062). For example, the first reaction may be carried out in a reaction inert solvent such as THF, acetonitrile or an alcohol (e.g., ethanol) at from about room temperature to about 100xc2x0 C. from about 30 minutes to 48 hours. The cyclization may be carried out in the presence of an alkyl halide at from about 0xc2x0 C. to reflux temperature from about 30 minutes to 48 hours.
(b) The compound of formula Ia14 may be treated with appropriate alkyl halides in the presence of a base such as lithium diisopropyl amide (LDA), sodium hydride (NaH) or potassium t-butoxide in a reaction inert solvent such as hexamthylphosphorous triamide(HMPT), THF or DMF at about 0xc2x0 C. to about 100xc2x0 C. for about 5 minutes to about 48 hours. 
Reaction Scheme 18 illustrates a method for the preparation of the compound of formula (I) wherein R1 is R18S (R18 is C18 alkyl), A is phenyl, B is ethylene and W is O or R1axe2x80x94N (R1a is H or C1-4alkyl) (hereinafter represented by Formula (Ia17)).
Compound (Ia17) may be prepared through the process comprising:
(a) 2-amino-benzimidazole or 2-amino-imidazopyridine ring formation with a compound of formula 18-1 to give a compound of formula (Ia16); and
(b) alkylation of the compound of formula (Ia16) to give a compound of formula (Ia17).
Each reaction step is described more specifically as follows.
(a) The compound of formula 18-1 may be subjected to a reaction with an thiocarbonyl reagent such as 1,1-thiocarbonylimidazole or di(2-pyridyl)thionocarbonate to give the compound of formula (Ia16) (e.g., Y. Abe, H. Kayakiri, S. Satoh et al., J. Med. Chem. 1998, 41, 4062). For example, the reaction may be carried out in a reaction inert solvent such as THF, acetonitrile, dichloromethane or an alcohol (e.g., ethanol) at from about room temperature to about 100xc2x0 C. from about 30 minutes to 48 hours. The cyclization may be carried out in the presence of an alkyl halide at from about 0xc2x0 C. to reflux temperature from about 30 minutes to 48 hours.
(b) The compound of formula (Ia16) may be treated with appropriate alkyl halides in the presence of a base such as potassium carbonate, lithium diisopropyl amide (LDA), sodium hydride (NaH) or potassium t-butoxide in a reaction inert solvent such as hexamthylphosphorous triamide (HMPT), THF or DMF at about 0xc2x0 C. to about 100xc2x0 C. for about 5 minutes to about 48 hours. 
As shown in Scheme 19, the compound of formula 19-3 (1-5) may also be prepared by reacting a compound of formula 19-1 with a substituted benzene compound of formula 19-2 to give a 1-phenylbenzimidazole compound of formula 19-3; The compounds of formula 19-1 may be synthesized by any of the known methods. The group G19 of the compounds of formula 19-2 is a selected from a suitable displaceable group, for example, fluoro, chloro, bromo, iodo, trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy, or boronic acid group. 
The coupling reaction may be carried out in the presence of a base in a reaction inert solvent. A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or dimethylaminopyridine. Preferred reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, pyridine, dichloromethane, 1,2-dichloroethane, tetrahyrofuran, acetonitrile, dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 150xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to several weeks, preferably from 20 minutes to 1 week, however shorter or longer reaction times, if necessary, can be employed. Conveniently, the compound of formula 19-1 may be reacted with the compound of formula 19-2 in the presence of a suitable catalyst to form the compound of formula 19-3 by any synthetic procedure applicable to structure-related compounds known to those skilled in the literature (e.g., Lam, P. Y. S.; Clark, C. G.; Saubern, S; Adams, J; Winters, M. P.; Chan, D. M. T.; Combs, A., Tetrahedron Lett., 1998, 39, 2941-2944., Kiyomori, A.; Marcoux, J.; Buchwald, S. L., Tetrahedron Lett., 1999, 40, 2657-2660., Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong, P.; Clark, C. G., J. Am. Chem. Soc., 2000, 122, 7600-7601., Collman, J. P.; Zhong, M., Org. Lett., 2000, 2, 1233-1236.). Preferred reaction catalyst is selected from, for example, but not limited to, tetrakis(triphenylphosphine)-palladium, bis(triphenylphosphine)palladium(II) chloride, copper(I), copper(I) acetate, copper(I) bromide, copper(I) chloride, copper(I) iodide, copper(I) oxide, copper(I) trifluoromethanesulfonate, copper(II) acetate, copper(II) bromide, copper(II) chloride, copper(II) iodide, copper(II) oxide, or copper(II) trifluoromethanesulfonate.
As shown in Scheme 20, the compound of formula 1-5 or 1e-4 may also be prepared through the process comprising:
(a) acylation of a compound of formula 20-1;
(b) benzimidazole or imidazopyridine ring cyclization of a compound of formula 20-2 to give a compound of formula 20-3. 
Each reaction step is described more specifically as follows.
(a) A compound of formula 20-1 (1-3 or 1e-3) is reacted with an appropriate acylating reagent to give a compound of formula 20-2 in a reaction inert solvent in the presence of, or absence of a coupling reagent and/or additive. Suitable acylating reagents include, but are not limited to, a carboxylic acid, an amino carboxylic acid, an acid anhydride (e.g., acetic anhydride, isobutyric anhydride, benzoic anhydride, isonicotinic anhydride and the like) a formamidine (e.g., formamidine alkylate such as formamidine acetate), an alkyl carbonyl halide (e.g., a cycloalkyl carbonyl halide, bicyclic, heterocyclic, or bicyclic-heterocyclic-carbonyl halide, spirocarbocyclic- or spiro-heterocyclic-carbonyl halide), an aryl or an aryl alkyl carbonyl halide (e.g., phenylacethyl halide), an heteroaryl carboxylic acid (e.g., a piperidinyl carboxylic acid compound), trialkyl orthoformate (e.g., triethyl orthoformate), and the like. Suitable reaction inert solvents include, but are not limited to, benzene, toluene, xylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran (THF), dimethylformamide (DMF), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. Suitable coupling reagents are those typically used in peptide synthesis including, but are not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphorylazide (DPPA), N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium hexafluorophosphate (HBTU), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), bromo[tri(1-pyrrolidinyl)]phosphonium hexafluorophosphate (PyBroP), bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (BOP-Cl), (1H-1,2,3-benzotriazol-1-yloxy)[tri(1-pyrrolidinyl)]phosphonium hexafluorophosphate (PyBOP), or the like. Suitable additives include, but are not limited to, 1H-1,2,3-benzotriazol-1-ol (HOBt), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt), N,N-dimethyl-4-pyridinamine (DMAP), or the like. The reaction may be carried out at a temperature in the range from of xe2x88x92100xc2x0 C. to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a few days, preferably from 30 minutes to 48 hours, however shorter or longer reaction times, if necessary, can be employed.
(b) The resulting amide compound of formula 20-2 may also be cyclized to form a benzimidazole or imidazopyridine ring in the presence of a base (Bashir, M.; Kingston, D. G. I.; Carman, R. J.; Van Tassell, R. L.; Wilkins, T. D.,: Heterocycles, 1987, 26, 2877-2886.). A preferred base is selected from, for example, but not limited to, an alkali or alkaline earth metal hydroxide, alkoxide, or carbonate, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, or potassium carbonate, in a reaction inert solvent. Preferred reaction inert solvents include, but are not limited to, water, methanol, ethanol, tetrahyrofuran (THF), benzene, toluene, xylene, dichloromethane, ethyleneglycol, or mixtures thereof. Reaction temperatures are generally in the range of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0 to 70xc2x0 C., but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 hour to 5 days, preferably from 3 hours to 2 days, however shorter or longer reaction times, if necessary, can be employed.
As shown in Scheme 21, an intermediate compound of formula 21-2 (1-4 or 1e-4) may also be prepared. 
The compound of formula 21-1 may be reacted with an appropriate aldehyde in a reaction inert solvent in the presence of, or absence of acid to produce an intermediate Shiff base. Succeedingly, the Shiff base can be oxidativery cyclized to form a benzimidazole or imidazopyridine ring by iodine, sulfur, cupric acetate, mercuric oxide, chloranil, active manganese dioxide, lead tetraacetate, nickel peroxide, barium permanganate, or the like. Suitable reaction inert solvents include, but are not limited to, methanol, ethanol, water, benzene, toluene, xylene, mesitylene, o-dichlorobenzene, nitrobenzene, dichloromethane, 1,2-dichloroethane, tetrahyrofuran (THF), dimethoxyethane (DME), 1,4-dioxane, dimethylsulfoxide (DMSO) or mixtures thereof. The reaction may be carried out at a temperature in the range from of xe2x88x92100 to 250xc2x0 C., preferably in the range of 0xc2x0 C. to the reflux temperature, but if necessary, lower or higher temperature can be employed. Reaction times are, in general, from 1 minute to a few days, preferably from 30 minutes to 48 hours, however shorter or longer reaction times, if necessary, can be employed.
Also, the aryl or heteroaryl fused imidazole comopounds of Formula (II) of this invention may be prepared by a variety of synthetic methods known to those skilled in the art. 
Reaction Scheme 22 illustrates a method for the preparation of the compound of formula (II). 
The compound of formula (II) may be prepared from the compound of 22-1(1-1) according to the similar procedure to that of described in Scheme 1.
Also, the aryl or heteroaryl comopounds of Formula (III) of this invention may be prepared by a variety of synthetic methods known to those skilled in the art. 
Reaction Scheme 23 illustrates a method for the preparation of the compound of formula (II). 
The compound of formula (III) may be prepared from the compound of 23-1(22-3) according to the similar procedure to that of described in Scheme 20.
In addition, the benzimidazole moiety of the compound of formula (I) which can be used herein may be prepared by known methods as shown in, for example: (1) Grimmett, M. R. Imidazoles and Their Benzo Derivatives: (iii) Synthesis and Applications. In Comprehensive Heterocyclic Chemistry, Kevin T. Potts, Eds.; Pergamon Press Ltd.: Oxford, UK, 1984; Vol.5, pp457-498; (2) Grimmett, M. R. Imidazoles. In Comprehensive Heterocyclic Chemistry II, Ichiro Shinkai, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.3, pp77-220.
The imidazopyridine moiety of the compound of formula (I) which can be used herein may be prepared by known methods as shown in, for example: Townsend L. B; Wise D. S. Bicyclo 5-6 Systems: Three Heteroatoms 2:1. In Comprehensive Heterocyclic Chemistry II, Christopher A. Ramsden, Eds.; Elsevier Science Ltd.: Oxford, UK, 1996; Vol.7, pp283-349.
The starting materials 1-1, 1-8, 1-9, 1a-2, 1d-3, 1d-4, 1d-5, 1d-6, 1f-0, 2-2, 5-4, 15-1, 15-3, 22-0 and the other reactants are known or commercially available compounds, or may be prepared according to known procedures for a person skilled in the art.
The subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assay. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of presentation and detectability. Further, substitution with heavier isotopes such as deutrium, i.e., 2H, can afford therapeutic advantage resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirement and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedure disclosed in above-disclosed Schemes and/or Examples and Preparations below, by submitting a readily available isotopically labelled reagent for a non-isotopically labeled reagent.
The present invention includes salt forms of the compounds (I) as obtained Certain compounds of the present invention are capable of forming pharmaceutically acceptable non-toxic cations. Pharmaceutically acceptable non-toxic cations of compounds of formula (I) may be prepared by conventional techniques by, for example, contacting said compound with a stoichiometric amount of an appropriate alkali or alkaline earth metal (sodium, potassium, calcium and magnesium) hydroxide or alkoxide in water or an appropriate organic solvent such as ethanol, isopropanol, mixtures thereof, or the like.
The bases which are used to prepare the pharmaceutically acceptable base addition salts of the acidic compounds of this invention of formula (I) are those which form non-toxic base addition salts, i.e., salts containing pharmaceutically acceptable cations, such as adenine, arginine, cytosine, lysine, benethamine(i.e., N-benzyl-2-phenyletylamine), benzathine(i.e., N,N-dibenzylethylenediamine), choline, diolamine(i.e., diethanolamine), ethylenediamine, glucosamine, glycine, guanidine, guanine, meglumine(i.e., N-methylglucamine), nicotinamide, olamine(i.e., ethanolamine), ornithine, procaine, proline, pyridoxine, serine, tyrosine, valine and tromethamine(i.e., tris or tris(hydroxymethyl)aminomethane). The base addition salts can be prepared by conventional procedures.
Insofar as the certain compounds of this invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the basic compounds of this invention of formula (I) are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, malate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, adipate, aspartate camsylate, (i.e., 1,2-ethanedisulfontate), estolate(i.e., laurylsulfate), gluceptate(i.e., gluscoheptonate), gluconate, 3-hydroxy-2-naphthoate, xionofoate(i.e., 1-hydrroxy-2-naphthoate), isethionate,(i.e., 2-hydroxyethanesulfonate), mucate(i.e., galactarate), 2-naphsylate(i.e., naphthalenesulphonate, stearate, cholate, glucuronate, glutamate, hippurate, lactobionate, lysinate, maleate, mandelate, napadisylate, nicatinate, polygalacturonate, salicylate, sulphosalicylate, tannate, tryptophanate, borate, carbonate, oleate, phthalate and pamoate (i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate). The acid addition salts can be prepared by conventional procedures.
Also included within the scope of this invention are bioprecursors (also called pro-drugs) of the compounds of the formula (I). A bioprecursor of a compound of the formula (I) is a chemical derivative thereof which is readily converted back into the parent compound of the formula (I) in biological systems. In particular, a bioprecursor of a compound of the formula (I) is converted back to the parent compound of the formula (I) after the bioprecursor has been administered to, and absorbed by, a mammalian subject, e.g., a human subject. For example, it is possible to make a bioprecursor of the compounds of formula (I) in which one or both of L and W includes hydroxy groups by making an ester of the hydroxy group. When only one of L and W includes hydroxy group, only mono-ester are possible. When both L and W include hydroxy, mono- and di-esters (which can be the same or different) can be made. Typical esters are simple alkanoate esters, such as acetate, propionate, butyrate, etc. In addition, when L or W include a hydroxy group, bioprecursors can be made by converting the hydroxy group to an acyloxymethyl derivative (e.g., a pivaloyloxymethyl derivative) by reaction with an acyloxymethyl halide (e.g., pivaloyloxymethyl chloride).
When the compounds of the formula (I) of this invention may form solvates such as hydrates, such solvates are included within the scope of this invention.
Also, the compounds of formula (I) may be expected more effective therapeutic effects with being co-administered with a COX-2 selective NSAID.
Further, the present invention also encompasses a pharmaceutical composition for the treatment of inflammation, rheumatoid arthritis, pain, common cold, osteoarthritis, neuropathic pain, brain tumor, diuresis, or the like, which comprises a therapeutically effective amount of the aryl or heteroaryl fused imidazole compound of formula (I) and a COX-2 selective NSAID or their pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
The compounds of the invention may advantageously be employed in combination with one or more other therapeutic ingredients selected from, a COX-2 selective, COX-1 selective or non-selective NSAIDs, opioids, anticonvulsants, antidepressants, local anesthetics, disease-modifying anti-rheumatoid drugs, or steroid.
The combination with a COX-2 selective NSAID is particularly favorured for use in the prophylaxis and treatment of pain and arthritis. Examples of a COX-2 selective NSAID are nimesulide, celecoxib, rofecoxib and valdecoxib.
The compounds of Formula (I) have been found to possess an activity as prostaglandin E2 receptor antagonist, preferably as EP4 receptor antagonist. Preferably, these compounds are useful as an analgesic, anti-inflammatory, diuretic, and the like, in mammalian subjects, especially humans in need of such agents. The affinity, antagonist activities and analgesic activity can be demonstrated by the following tests respectively.
In vitro Assays
Rat EP Receptor Cell Membrane Binding Assay
Stable Expression of Rat EP1, 2, 3 and 4 Receptors in the Human Embryonic Kidney (HEK293) Cell Line
The cDNA clones of rat EP1, 2, 3 and 4 receptors are obtained by polymerase chain reaction (PCR) from rat kidney or heart cDNA libraries (Clontech). Human embryonic kidney cells (HEK 293) are stably transfected with expression vectors for rat EP1, 2, 3 and 4 receptors in according to the method described in the article; the journal of biological chemistry vol.271 No.39, pp23642-23645.
Preparation of Membrane Fraction
The EP1, 2, 3 and 4 transfectant are grown in Dulbecco""s modified Eagle""s medium containing 10% fetal calf serum, 100 U/ml penicillin, 100 xcexcg/ml streptomycin and 600 xcexcg/ml G418 (selection medium) at 37xc2x0 C. in a humidified atmosphere of 5% CO2 in air. For the membrane preparation, cells are harvested with phosphate buffered saline (PBS) and centrifuged at 400xc3x97g for 5 min. The pellet is suspended with child (4xc2x0 C.) PBS containing 1 mM Pefabloc (4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF)), 10 xe2x96xa1M Phosphoramidon, 1 xe2x96xa1M Pepstatin A, 10 xe2x96xa1M Elastatinal, 100 xe2x96xa1M Antipain. Cells are lysed with ultrasonic cell disrupter for 20-sec sonication. Then cell mixtures are centrifuged at 45,000xc3x97g for 30 minutes. The pellet is resuspended in assay buffer (10 mM 2-morpholinoeth-anesulfonic acid (MES)-KOH, 1 mM etylenediamine tetra-acetic acid (EDTA), 10 mM MgCl2, pH 6.0), and protein concentration is determined by Bradford method (Bio-Rad assay). This membrane preparation is stored at xe2x88x9280xc2x0 C. freezer until use for binding assay.
Binding Assay
Membrane Binding Assay
[3H]-PGE2 membrane binding assays are performed in the reaction mixture of 10 mM MES/KOH (pH6.0), 10 mM MgCl2, 1 mM EDTA, 1 nM [3H]-PGE2 (Amersham TRK431, 164 Ci/mmol), 2xcx9c10 xe2x96xa1g of protein from membrane fraction (rat EP1, 2, 3 and 4/HEK293 transfectant) and test compound (total volume is 0.1 ml in 96 well polypropylene plate). Incubation is conducted for 60 min at room temperature prior to separation of the bound and free radioligand by rapid filtration through glass fiber filters (Printed Filtermat B, 1205-404, glass fiber, double thickness, size 102xc3x97258 mm, Wallac inc., presoaked in 0.2% polyethylenimine). Filters are washed with assay buffer and the residual [3H]-PGE2 bound to the filter is determined by liquid scintillation counter (1205 Betaplate(trademark)). Specific binding is defined as the difference between total binding and nonspecific binding which is determined in the presence of 10 xe2x96xa1M PGE2.
cAMP Assay in Rat EP4 Transfectant
HEK293 cells expressing rat EP4 receptors (rEP4 cells) are maintained in DMEM containing 10% FCS and 600 xe2x96xa1g/ml geneticin. For harvesting rEP4 cells, culture medium is aspirated and cells in 75 cm2 flask are washed with 10 ml of phosphate buffered saline (PBS). Another 10 ml of PBS is added to the cells and incubated for 20 min at room temperature. Rat EP4 cells are harvested by pipetting and centrifuged at 300 g for 4 min. Cells are resuspended in DMEM without neutral red at a density of 5xc3x97105 cells/ml. The cells (70 xe2x96xa1l) are mixed with 70 xe2x96xa1l of DMEM (without neutral red) containing 2 mM IBMX (PDE inhibitor), 1 nM PGE2 and test compounds in PCR-tubes, and incubated at 37xc2x0 C. for 10 min. The reaction is stopped by heating at 100xc2x0 C. for 10 min with thermal cycler. Concentration of cAMP in reaction mixtures is determined with SPA cAMP Kit (Amersham) according to the manufacture""s instruction.
Reference: Eur.J.Pharmacol. 340 (1997) 227-241
In vivo Assays
Carrageenan Induced Mechanical Hyperalgesia in Rats
Male 4-week-old SD rats (Japan SLC) were fasted over night. Hyperalgesia was induced by intraplantar injection of xcex-carrageenin (0.1 ml of 1% w/v suspension in saline, Zushikagaku). The test compounds (1 ml of 0.1% methylcellulose/100 g body weight) were given per orally at 5.5 hours after the carrageenin injection. The mechanical pain threshold was measured by analgesy meter (Ugo Basile) at 4, 5, 6.5 and 7.5 hours after the carrageenin injection and the change of pain threshold was calculated.
Reference: Randall L. O. and Selitto I. J., Arch. Int. Pharmacodyn. 111, 409-419, 1957
Prostaglandin E2(PGE2)-Induced Thermal Hyperalgesia in Rats
Male 4-week-old SD rats (Japan SLC) were fasted over night. Hyperalgesia was induced by intraplantar injection of 100 ng of PGE2 in 5% DMSO/saline(100 ul) into the right hindpaw of the rats. Animals were given orally or intravenously either vehicle (po: 0.1% methyl cellulose, iv: 10% DMSO/saline) or a test compound 15 or 5 min. prior to PGE2 injection, respectively. Rats were placed in plastic cages of plantar test apparatus (Ugo Basile) and the mobile radiant heat source was focused on right hind paw of the rats. The thermal paw-withdrawal latency (sec.) was measured at 15 min after PGE2 injection and the change in withdrawal threshold was calculated.
Reference: Hargreaves K. et al., Pain 32, 77-88, 1988.
Most of the compounds prepared in the working examples appearing hereafter demonstrate higher affinity for EP4-receptors than for EP1, 2 and 3-receptors.
Some preferred compounds prepared in the working examples as described below were tested by the above method, and showed an ED50 value under 60 mg/kg.
The aryl or heteroaryl fused imidazole compounds of formula (I) of this invention can be administered via either the oral, parenteral or topical routes to mammals. In general, these compounds are most desirably administered to humans in doses ranging from 0.1 mg to 3000 mg, preferably from 1 mg to 500 mg, which may be administered in a single dose or in divided doses throughout the day, although variations will necessarily occur depending upon the weight and condition of the subject being treated, the disease state being treated and the particular route of administration chosen. However, for example, a dosage level that is in the range of from 0.01 mg to 10 mg per kg of body weight per day is most desirably employed for treatment of pain associated with inflammation.
The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging 5% to 95% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dipotassium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.